Method for producing an optically active tetrahydroquinoline

ABSTRACT

The present invention provides an industrially advantageous production method of optically active tetrahydroquinolines of formula (1), 
                         
which comprises:
     1) a step of reacting a β-ketoester of formula (2)   
     
       
         
         
             
             
         
       
         
          with an amine of formula (3) 
       
    
     
       
         
         
             
             
         
       
         
          to produce an enaminoester of formula (4); 
       
    
     
       
         
         
             
             
         
       
         
         2) a step of subjecting the enaminoester of formula (4) above obtained in 1) to asymmetric hydrogenation to produce an optically active β-amino acid derivative of formula (5); 
       
    
     
       
         
         
             
             
         
       
         
         3) a step of amidating the optically active β-amino acid derivative (5) above obtained in 2) to produce an amide of formula (6); 
       
    
     
       
         
         
             
             
         
       
         
         4) a step of alkoxycarbonylating the amide of formula (6) above obtained in 3) to produce a compound of formula (7); 
       
    
     
       
         
         
             
             
         
       
         
          and 
         5) a step of subjecting the compound of formula (7) above to cyclization to produce the optically active tetrahydroquinoline of formula (1).

TECHNICAL FIELD

The present invention relates to a method for producing optically activetetrahydroquinolines which are useful, for example, as intermediates forthe synthesis of pharmaceuticals, agrochemicals, etc.

BACKGROUND ART

In recent years, tetrahydroquinolines are widely used aspharmaceuticals, etc., and a variety of methods for producing them havebeen studied.

Production methods of tetrahydroquinolines via amino acid derivatives asintermediates have been disclosed (patent references 1 and 2, etc).

The patent references 1 and 2 disclose production methods oftetrahydroquinolines in which secondary amines obtained by the reactionsof primary amines with aryl halogenides are used as the startingmaterial. However, those methods require that the reaction conditionsare selected so as not to bring about racemization in the process ofintroducing an alkyl or aryl group onto the amino group of opticallyactive primary amines such as amino acids.

The non-patent reference 1 discloses a method for producing opticallyactive amino acids in which the amino group is a secondary one by way ofan asymmetric nucleophilic addition to the imines. However, forobtaining the desired amines, it is indispensable to use an excessamount of flammable diethylzinc, which has drawbacks in the workability,etc. of the reaction.

The non-patent reference 2 discloses a method for producing β-amino acidderivatives, in which enamines obtained by substituting the remaininghydrogen atom of a secondary amino group with an acetyl group, to anasymmetric hydrogenation. However, the method of the non-patentreference 2 has a drawback of requiring protection of the secondaryamino group with a protecting group such as an acetyl group, etc.,before subjecting the enamines to asymmetric hydrogenation, thus makingtwo extra processes of introduction and removal of the protecting groupindispensable.

Patent reference 1: WO02/088069

Patent reference 2: WO02/088085

Non-patent reference 1: Chemistry Letters, 254-255 (2001).

Non-patent reference 2: Tetrahedron Asymmetry, Vol. 2, No. 7, 543-554(1991).

DISCLOSURE OF THE INVENTION

The present invention has been worked out in consideration of theproblem mentioned above, and the aim of the present invention is toprovide a method for producing optically active tetrahydroquinolineswhich does not require extra steps of introduction and removal of theprotecting group, in its excellent workability and good asymmetric andchemical yields.

The present inventors have intensively studied on the method forproducing optically active tetrahydroquinolines and found that theproblem mentioned above can be solved by using the enaminoesters andoptically active β-amino acid derivatives both of which are mentionedabove as intermediates and have worked out the present invention.

Thus, the present invention is as follows:

(1) A method for producing an optically active tetrahydroquinoline offormula (1),

wherein R¹ is a hydrocarbon group, a substituted hydrocarbon group orCOOR⁹ (R⁹ is a hydrocarbon group or a substituted hydrocarbon group); R⁴to R⁷ are each independently a hydrogen atom, a hydrocarbon group, ahalogen atom, a halogenated hydrocarbon group, a substituted hydrocarbongroup, an aliphatic heterocyclic group, a substituted aliphaticheterocyclic group, an aromatic heterocyclic group, a substitutedaromatic heterocyclic group, an alkoxy group, a substituted alkoxygroup, an aralkyloxy group, a substituted aralkyloxy group, an aryloxygroup, a substituted aryloxy group, an acyl group, an acyloxy group, analkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonylgroup, an alkylenedioxy group, a hydroxy group, a nitro group, an aminogroup or a substituted amino group; R⁸ is a hydrocarbon group or asubstituted hydrocarbon group; * shows an asymmetric carbon atom; and,R⁴ and R⁵, R⁵ and R⁶, or R⁶ and R⁷, taken together, may form a fusedring, which method comprises the following steps:

1) a step of reacting a β-ketoester of formula (2),

wherein R¹ is a hydrocarbon group, a substituted hydrocarbon group orCOOR⁹ (wherein R⁹ is a hydrocarbon group or a substituted hydrocarbongroup) and R² is a hydrocarbon group or a substituted hydrocarbon group,to react with an amine of formula (3),

wherein R³ to R⁷ are each independently a hydrogen atom, a hydrocarbongroup, a halogen atom, a halogenated hydrocarbon group, a substitutedhydrocarbon group, an aliphatic heterocyclic group, a substitutedaliphatic heterocyclic group, an aromatic heterocyclic group, asubstituted aromatic heterocyclic group, an alkoxy group, a substitutedalkoxy group, an aralkyloxy group, a substituted aralkyloxy group, anaryloxy group, a substituted aryloxy group, an acyl group, an acyloxygroup, an alkoxycarbonyl group, an aryloxycarbonyl group, anaralkyloxycarbonyl group, an alkylenedioxy group, a hydroxy group, anitro group, an amino group or a substituted amino group; and, R³ andR⁴, R⁴ and R⁵, R⁵ and R⁶, or R⁶ and R⁷, taken together, may form a fusedring, with the proviso that either R³ or R⁷ is a hydrogen atom, toproduce an enaminoester of formula (4),

wherein R¹ to R⁷ are each the same meaning as mentioned above;

2) a step of subjecting the enaminoester of formula (4) above obtainedin 1) to an asymmetric hydrogenation to produce an optically activeβ-amino acid derivative of formula (5),

wherein * shows an asymmetric carbon atom and R¹ to R⁷ are each the samemeaning as mentioned above;

3) a step of amidating the optically active β-amino acid derivative offormula (5) above obtained in 2) above, to produce an amide of formula(6),

wherein, R¹, R³ to R⁷ and * have the same meanings as mentioned above;

4) a step of alkoxycarbonylating the amide of formula (6) above obtainedin 3) above, to produce a compound of formula (7),

wherein R⁸ is a hydrocarbon group or a substituted hydrocarbon group,and R¹, R³ to R⁷ and * have the same meanings as mentioned above; and

5) a step of subjecting the compound of formula (7) above obtained in 4)above to a cyclization to produce an optically activetetrahydroquinoline of formula (1) above.

(2) A method for producing an optically active tetrahydroquinoline offormula (1),

wherein, R¹ is a hydrocarbon group, a substituted hydrocarbon group orCOOR⁹ (R⁹ is a hydrocarbon group or a substituted hydrocarbon group), R⁴to R⁷ are each independently a hydrogen atom, a hydrocarbon group, ahalogen atom, a halogenated hydrocarbon group, a substituted hydrocarbongroup, an aliphatic heterocyclic group, a substituted aliphaticheterocyclic group, an aromatic heterocyclic group, a substitutedaromatic heterocyclic group, an alkoxy group, a substituted alkoxygroup, an aralkyloxy group, a substituted aralkyloxy group, an aryloxygroup, a substituted aryloxy group, an acyl group, an acyloxy group, analkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonylgroup, an alkylenedioxy group, a hydroxy group, a nitro group, an aminogroup or a substituted amino group; R⁸ is a hydrocarbon group or asubstituted hydrocarbon group; * shows an asymmetric carbon atom; and R⁴and R⁵, R⁵ and R⁶, or R⁶ and R⁷, taken together, may form a fused ring,which method comprises the following steps:

1) a step of reacting a β-ketoester of formula (2),

wherein R¹ is a hydrocarbon group, a substituted hydrocarbon group orCOOR⁹ (R⁹ is a hydrocarbon group or a substituted hydrocarbon group, andR² is a hydrocarbon group or a substituted hydrocarbon group) with anamine of formula (3),

wherein R³ to R⁷ are each independently a hydrogen atom, a hydrocarbongroup, a halogen atom, a halogenated hydrocarbon group, a substitutedhydrocarbon group, an aliphatic heterocyclic group, a substitutedaliphatic heterocyclic group, an aromatic heterocyclic group, asubstituted aromatic heterocyclic group, an alkoxy group, a substitutedalkoxy group, an aralkyloxy group, a substituted aralkyloxy group, anaryloxy group, a substituted aryloxy group, an acyl group, an acyloxygroup, an alkoxycarbonyl group, an aryloxycarbonyl group, anaralkyloxycarbonyl group, an alkylenedioxy group, a hydroxy group, anitro group, an amino group or a substituted amino group; R³ and R⁴, R⁴and R⁵, R⁵ and R⁶, or R⁶ and R⁷, taken together, may form a fused ring,with the proviso that either R³ or R⁷ is a hydrogen atom, to produce anenaminoester of formula (4),

wherein, R¹ to R⁷ have the same meanings as mentioned above;

2) a step of subjecting the enaminoester of formula (4) above obtainedin 1) above to asymmetric hydrogenation to produce an optically activeβ-amino acid derivative of formula (5),

wherein * shows an asymmetric carbon atom and R¹ to R⁷ have the samemeanings as those mentioned above;

3) a step of reacting the optically active β-amino acid derivativeobtained in 2) with a carbamate of formula (8),H₂N—COOR⁸  (8)wherein R⁸ is a hydrocarbon group or a substituted hydrocarbon group, toproduce a compound of formula (7),

wherein R⁸ is a hydrocarbon group or a substituted hydrocarbon group,and R¹, R³ to R⁷ and * have the same meanings as mentioned above; and

4) a step of subjecting the optically active compounds of formula (7)above obtained in 3) above to a cyclization to produce an opticallyactive tetrahydroquinoline of formula (1) above.

(3) A method for producing an optically active tetrahydroquinoline offormula (1),

wherein, R¹ is a hydrocarbon group, a substituted hydrocarbon group orCOOR⁹ (R⁹ is a hydrocarbon group or a substituted hydrocarbon group), R⁴to R⁷ are each independently a hydrogen atom, a hydrocarbon group, ahalogen atom, a halogenated hydrocarbon group, a substituted hydrocarbongroup, an aliphatic heterocyclic group, a substituted aliphaticheterocyclic group, an aromatic heterocyclic group, a substitutedaromatic heterocyclic group, an alkoxy group, a substituted alkoxygroup, an aralkyloxy group, a substituted aralkyloxy group, an aryloxygroup, a substituted aryloxy group, an acyl group, an acyloxy group, analkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonylgroup, an alkylenedioxy group, a hydroxy group, a nitro group, an aminogroup or a substituted amino group; R⁸ is a hydrocarbon group or asubstituted hydrocarbon group; * shows an asymmetric carbon atom; and R⁴and R⁵, R⁵ and R⁶, or R⁶ and R⁷, taken together, may form a fused ring,which method comprises the following steps:

1) a process of subjecting the enaminoester of formula (4),

wherein R¹ is a hydrocarbon group, a substituted hydrocarbon group orCOOR⁹ (R⁹ is a hydrocarbon group or a substituted hydrocarbon group), R²is a hydrocarbon group or a substituted hydrocarbon group; R³ to R⁷ areeach independently a hydrogen atom, a hydrocarbon group, a halogen atom,a halogenated hydrocarbon group, a substituted hydrocarbon group, analiphatic heterocyclic group, a substituted aliphatic heterocyclicgroup, an aromatic heterocyclic group, a substituted aromaticheterocyclic group, an alkoxy group, a substituted alkoxy group, anaralkyloxy group, a substituted aralkyloxy group, an aryloxy group, asubstituted aryloxy group, an acyl group, an acyloxy group, analkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonylgroup, an alkylenedioxy group, a hydroxy group, a nitro group, an aminogroup or a substituted amino group; R³ and R⁴, R⁴ and R⁵, R⁵ and R⁶, orR⁶ and R⁷, taken together, may form a fused ring, with the proviso thateither R³ or R⁷ is a hydrogen atom, to an asymmetric hydrogenation toproduce an optically active β-amino acid derivative of formula (5),

wherein * shows an asymmetric carbon atom, and R¹ to R⁷ have the samemeanings as mentioned above;

2) a step of amidating the optically active β-amino acid derivative offormula (5) above obtained in 1) above to produce an optically activeamide of formula (6),

wherein R¹, R³ to R⁷ and * have the same meanings as mentioned above,

3) a step of alkoxycarbonylating the optically active amide of formula(6) above obtained in 2) above to produce a compound of formula (7),

wherein R⁸ is a hydrocarbon group or a substituted hydrocarbon group,and R¹, R³ to R⁷ and * have the same meanings as mentioned above; and

4) a step of subjecting the optically active compounds of formula (7)above obtained in 3) above to a cyclization to produce an opticallyactive tetrahydroquinoline of formula (1) above.

(4) A method for producing an optically active tetrahydroquinoline offormula (1),

wherein R¹ is a hydrocarbon group, a substituted hydrocarbon group orCOOR⁹ (R⁹ is a hydrocarbon group or a substituted hydrocarbon group), R⁴to R⁷ are each independently a hydrogen atom, a hydrocarbon group, ahalogen atom, a halogenated hydrocarbon group, a substituted hydrocarbongroup, an aliphatic heterocyclic group, a substituted aliphaticheterocyclic group, an aromatic heterocyclic group, a substitutedaromatic heterocyclic group, an alkoxy group, a substituted alkoxygroup, an aralkyloxy group, a substituted aralkyloxy group, an aryloxygroup, a substituted aryloxy group, an acyl group, an acyloxy group, analkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonylgroup, an alkylenedioxy group, a hydroxy group, a nitro group, an aminogroup or a substituted amino group; R⁸ is a hydrocarbon group; * showsan asymmetric carbon atom; and, R⁴ and R⁵, R⁵ and R⁶, or R⁶ and R⁷,taken together, may form a fused ring, which method comprises thefollowing steps:

1) a step of subjecting an enaminoester of formula (4),

wherein R¹ is a hydrocarbon group, a substituted hydrocarbon group orCOOR⁹ (R⁹ is a hydrocarbon group or a substituted hydrocarbon group); R²is a hydrocarbon group or a substituted hydrocarbon group; R³ to R⁷ areeach independently a hydrogen atom, a hydrocarbon group, a halogen atom,a halogenated hydrocarbon group, a substituted hydrocarbon group, analiphatic heterocyclic group, a substituted aliphatic heterocyclicgroup, an aromatic heterocyclic group, a substituted aromaticheterocyclic group, an alkoxy group, a substituted alkoxy group, anaralkyloxy group, a substituted aralkyloxy group, an aryloxy group, asubstituted aryloxy group, an acyl group, an acyloxy group, analkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonylgroup, an alkylenedioxy group, a hydroxy group, a nitro group, an aminogroup or a substituted amino group; and, R³ and R⁴, R⁴ and R⁵, R⁵ andR⁶, or R⁶ and R⁷, taken together, may form a fused ring, with theproviso that either R³ or R⁷ is a hydrogen atom, to an asymmetrichydrogenation to produce an optically active β-amino acid derivative offormula (5),

wherein * shows an asymmetric carbon atom, and R¹ to R⁷ have the samemeanings as described above;

2) a step of reacting the optically active β-amino acid derivative offormula (5) above obtained in 1) above with a carbamate of formula (8),H₂N—COOR⁸  (8)wherein R⁸ is a hydrocarbon group or a substituted hydrocarbon group, toproduce a compound of formula (7),

wherein R⁸ is a hydrocarbon group or a substituted hydrocarbon group,and R¹, R³ to R⁷ and * have the same meanings as mentioned above;

3) a step of subjecting the optically active compound of formula (7)above obtained in 2) above to a cyclization to produce an opticallyactive tetrahydroquinoline of the formula (1) mentioned above.

(5) A β-amino acid derivative of formula (15c),

wherein R²⁵ is a hydrocarbon group or COOR³² (R³² is a hydrocarbon groupor a substituted hydrocarbon group); R²⁶ is a hydrocarbon group or asubstituted hydrocarbon group; R²⁷ to R³¹ are each independently ahydrogen atom, a hydrocarbon group, a halogen atom, a halogenatedhydrocarbon group or an alkoxy group, with the proviso that i) eitherR²⁷ or R³¹ is a hydrogen atom ii) at least one of R²⁷ to R³¹ is ahydrocarbon group, a halogen atom, a halogenated hydrocarbon group or analkoxy group, iii) when at least one of R²⁷ to R³¹ is an alkoxy group,R²⁵ is a methyl group or an ethyl group, and iv) when at least one ofR²⁷ to R³¹ is a halogen atom or a methyl group, R²⁵ is a hydrocarbongroup.

(6) A method for producing an optically active β-amino acid derivativeof formula (5a),

wherein R is OR² (R² is a hydrocarbon group or a substituted hydrocarbongroup) or an amino group, R¹ is a hydrocarbon group, a substitutedhydrocarbon group or COOR⁹ (R⁹ is a hydrocarbon group or a substitutedhydrocarbon group); R³ to R⁷ are each independently a hydrogen atom, ahydrocarbon group, a halogen atom, a halogenated hydrocarbon group, asubstituted hydrocarbon group, an aliphatic heterocyclic group, asubstituted aliphatic heterocyclic group, an aromatic heterocyclicgroup, a substituted aromatic heterocyclic group, an alkoxy group, asubstituted alkoxy group, an aralkyloxy group, a substituted aralkyloxygroup, an aryloxy group, a substituted aryloxy group, an acyl group, anacyloxy group, an alkoxycarbonyl group, an aryloxycarbonyl group, anaralkyloxycarbonyl group, an alkylenedioxy group, a hydroxy group, anitro group, an amino group or a substituted amino group; R³ and R⁴, R⁴and R⁵, R⁵ and R⁶, or R⁶ and R⁷, taken together, may form a fused ring,with the proviso that either R³ or R⁷ is a hydrogen atom, which methodcomprises subjecting an enaminoester of formula (4a),

wherein * shows an asymmetric carbon atom; and R, R¹ and R³ to R⁷ havethe same meanings as mentioned above, to an asymmetric hydrogenation.

(7) An enaminoester of formula (9),

wherein R¹⁰ is a hydrocarbon group or COOR¹⁶ (R¹⁶ is a hydrocarbon groupor a substituted hydrocarbon group); R¹¹ is a hydrocarbon group or asubstituted hydrocarbon group; R¹² to R¹⁵ are each independently ahydrogen atom, a hydrocarbon group, an alkoxy group, a halogen atom or ahalogenated hydrocarbon group, with the proviso that at least one of R¹²to R¹⁵ is an alkoxy group, a halogen atom or a halogenated hydrocarbongroup, and that when at least one of R¹² to R¹⁵ is CF₃ or a bromineatom, R¹⁰ is a hydrocarbon group except for a methyl group, and when atleast one of R¹² to R¹⁵ is a halogen atom, R¹⁰ is a hydrocarbon groupexcept for a methyl group.

(8) A method for producing a β-amino acid derivative of formula (22),

wherein R²¹ is a hydrocarbon group; R²² is a hydrogen atom, ahydrocarbon group, a substituted hydrocarbon group, an aliphaticheterocyclic group, a substituted aliphatic heterocyclic group, anaromatic heterocyclic group, a substituted aromatic heterocyclic group,an alkoxy group, a substituted alkoxy group, an aralkyloxy group, asubstituted group, an alkoxycarbonyl group, an aryloxycarbonyl group, anaralkyloxycarbonyl group; R²³ is a hydrogen atom, a hydrocarbon group, asubstituted hydrocarbon group, an aliphatic heterocyclic group, asubstituted aliphatic heterocyclic group, an aromatic heterocyclicgroup, a substituted aromatic heterocyclic group, an alkoxy group, asubstituted alkoxy group, an aralkyloxy group, a substituted aralkyloxygroup, an aryloxy group, a substituted aryloxy group, an acyloxy group,an alkyloxycarbonyl group, an aryloxycarbonyl group or anaralkyloxycarbonyl group; R²⁴ is a hydrocarbon group, an alkoxy group, asubstituted alkoxy group, an aralkyloxy group, a substituted aralkyloxygroup, an aryloxy group, a substituted aryloxy group, an amino group ora substituted amino group; and, R²² and R²³, or R²³ and R²⁴, takentogether, may form a ring, which method comprises allowing an enaminocompound of formula (21),

wherein * shows a asymmetric carbon atom, and R²¹ to R²⁴ have the samemeanings as mentioned above, to an asymmetric hydrogenation.

BEST MODE FOR CARRYING OUT THE INVENTION

The following is the description about the individual groups in formulae(1) to (8) above and other formulae.

Examples of the hydrocarbon group include, for example, an alkyl group,an alkenyl group, an alkynyl group, an aryl group and an aralkyl group.

The alkyl groups may be a straight, branched or cyclic one of, forexample, 1 to 10 carbon atoms, and the specific examples thereof includegroups such as methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl,isobutyl, tert-butyl, n-pentyl, 2-pentyl, tert-pentyl, 2-methylbutyl,3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-hexyl, 3-hexyl,2-methylpentan-2-yl, 3-methylpentan-3-yl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 2-methylpentan-3-yl, heptyl, octyl,2-ethylhexyl, nonyl, decyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, etc. Among them, alkyl groups of 1 to 6 carbon atoms arepreferable.

The alkenyl groups may be a straight or branched one of, for example, 2to 10 carbon atoms, and the specific examples thereof include groupssuch as ethenyl, propenyl, 1-butenyl, 2-butenyl, pentenyl, hexenyl,heptenyl, octenyl, nonenyl, decenyl, etc. Among them, alkenyl groups of2 to 6 carbon atoms are preferable.

The alkynyl groups may be a straight or branched one of, for example, 2to 10 carbon atoms, and the specific examples thereof include groupssuch as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 3-butynyl, pentynyl,hexynyl, etc. Among them, alkynyl groups of 2 to 6 carbon atoms arepreferable.

The aryl groups are those of 6 to 14 carbon atoms, and the specificexamples thereof include groups such as phenyl, naphthyl, anthryl,biphenyl, etc.

The aralkyl group is the one which is formed by replacing at least onehydrogen atom of the alkyl groups mentioned above with an aryl groupmentioned above. Thus, aralkyl groups of 7 to 15 carbon atoms arepreferable. Specific examples of them include benzyl, 2-phenylethyl,1-phenylpropyl, 3-naphthylpropyl, etc.

The halogen atoms include fluorine, chlorine, bromine, iodine atoms,etc.

The halogenated alkyl groups are those of 1 to 10 carbon atoms which arederived from the alkyl groups mentioned above by replacing at least oneof their hydrogen atom(s) with halogen atom(s) (for example, fluorine,chlorine, bromine, iodine atoms, etc.). Specific examples of theminclude groups such as chloromethyl, bromomethyl, 2-chloroethyl,3-bromopropyl, fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl,fluoropentyl, fluorohexyl, fluoroheptyl, fluorooctyl, fluorononyl,fluorodecyl, difluoromethyl, difluoroethyl, fluorocyclohexyl,trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl,pentafluoroethyl, 3,3,4,4,4-pentafluorobutyl, perfluoro-n-propyl,perfluoroisopropyl, perfluoro-n-butyl, perfluoroisobutyl,perfluoro-tert-butyl, perfluoro-sec-butyl, perfluoro-n-pentyl,perfluoroisopentyl, perfluoro-tert-pentyl, perfluoro-n-hexyl,perfluoroisohexyl, perfluoroheptyl, perfluorooctyl, perfluorononyl,perfluorodecyl, 2-perfluorooctylethyl, perfluorocyclopropyl,perfluorocyclopentyl, perfluorocyclohexyl, etc.

Among these halogenated alkyl groups, those of 1 to 6 carbon atoms andperfluoloalkyl group are preferable and those of 1 to 3 carbon atoms aremore preferable. Furthermore, fluorine-containing alkyl groups of 1 to 3carbon atoms such as fluoromethyl, fluroethyl, fluoropropyl,difluoromethyl, difluoroethyl, trifluoromethyl, 2,2,2-trifluoroethyl,3,3,3-trifluoropropyl, pentafluoroethyl, perfluoro-n-propyl,perfluoroisopropyl, etc. are most preferable.

The acyl groups are a straight branched one of 1 to 18 carbon atomsderived from aliphatic or aromatic carboxylic acids, etc. Specificexamples of such acyl groups include groups such as formyl, acetyl,propionyl, butyryl, pivaloyl, pentanoyl, hexanoyl, lauroyl, stearoyl,benzoyl, etc.

The aliphatic heterocyclic groups are for example, 5- to 8-membered, ormore preferably, 5- to 6-membered monocyclic, polycyclic or fused-ringaliphatic heterocyclic groups which are composed of 2 to 14 carbonatoms, and, as heteroatoms, at least one, and more preferably 1 to 3heteroatoms such as nitrogen, oxygen, sulfur atoms, etc. Specificexamples of such aliphatic heterocyclic groups include, for example,2-oxo-pyrrolidinyl, piperidino, piperazinyl, morpholino, morpholinyl,tetrahydrofuryl, tetrahydropyranyl, etc.

The aromatic heterocyclic groups are, for example, 5- to 8-membered, ormore preferably, 5- to 6-membered monocyclic, polycyclic or fused-ringaromatic heterocyclic groups which are composed of 2 to 15 carbon atoms,and, as heteroatoms, at least one, and more preferably 1 to 3heteroatoms such as nitrogen, oxygen, sulfur atoms, etc. Specificexamples of such aromatic heterocyclic groups include, for example,furyl, thienyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, pyrazolyl,imidazolyl, oxazolyl, thiazolyl, benzofuryl, benzothienyl, quinolyl,isoquinolyl, quinoxalyl, phthalazyl, quinazolyl, naphthyridyl, cinnolyl,benzimidazolyl, benzoxazolyl, and benzothiazolyl.

The alkoxy groups may be straight, branched or cyclic alkoxy groups of,for example, 1 to 6 carbon atoms, and specific examples of such alkoxygroups include, for example, methoxy, ethoxy, n-propoxy, 2-propoxy,n-butoxy, 2-butoxy, isobutoxy, tert-butoxy, n-pentyloxy, 2-methylbutoxy,3-methylbutoxy, 2,2-dimethylpropyloxy, n-hexyloxy, 2-methylpentyloxy,3-methylpentyloxy, 4-methylpentyloxy, cyclohexyloxy, etc.

The aryloxy groups are those of, for example, 6 to 14 carbon atoms, andspecific examples of such aryloxy groups include phenyloxy, naphthyloxy,anthryloxy, etc.

The aralkyloxy groups are those of, for example, 7 to 12 carbon atoms,and specific examples of such aralkyloxy groups include benzyloxy,2-phenylethoxy, 1-phenylpropoxy, 2-phenylpropoxy, 3-phenylpropoxy,1-phenylbutoxy, 2-phenylbutoxy, 3-phenylbutoxy, 4-phenylbutoxy,1-phenylpentyloxy, 2-phenylpentyloxy, 3-phenylpentyloxy,4-phenylpentyloxy, 5-phenylpentyloxy, 1-phenylhexyloxy,2-phenylhexyloxy, 3-phenylhexyloxy, 4-phenylhexyloxy, 5-phenylhexyloxy,6-phenylhexyloxy, etc.

The alkoxycarbonyl groups may be straight, branched or cyclicalkoxycarbonyl groups of, for example, 2 to 19 carbon atoms, andspecific examples of such alkoxycarbonyl groups include methoxycarbonyl,ethoxycarbonyl, n-propoxycarbonyl, 2-propoxycarbonyl, n-butoxycarbonyl,tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl,2-ethylhexyloxycarbonyl, lauryloxycarbonyl, stearyloxycarbonyl,cyclohexyloxycarbonyl, etc.

The aryloxycarbonyl groups are those of, for example, 7 to 20 carbonatoms, and specific examples of such aryloxycarbonyl groups includephenoxycarbonyl, naphthyloxycarbonyl, etc.

The aralkyloxycarbonyl groups are those of, for example, 8 to 15 carbonatoms, and specific examples of such aralkyloxycarbonyl groups includebenzyloxycarbonyl, phenylethoxycarbonyl, 9-fluorenylmethyloxycarbonyl,etc.

The acyloxy groups are straight or branched ones of, for example, 2 to18 carbon atoms derived from carboxylic acids such as aliphaticcarboxylic acids and aromatic carboxylic acids, and specific examples ofsuch acyloxy groups include acetoxy, propionyloxy, butyryloxy,pivaloyloxy, pentanoyloxy, hexanoyloxy, lauroyloxy, stearoyloxy,benzoyloxy, etc.

Examples of the substituted hydrocarbon groups include substituted alkylgroups, substituted alkenyl groups, substituted alkynyl groups,substituted aryl groups and substituted aralkyl groups.

The substituted alkyl groups include the alkyl groups as mentionedabove, at least one of the hydrogen atoms of which are substituted witha substituent such as alkyl groups, alkoxy groups, halogen atoms, aminogroups or substituted amino groups, etc., wherein the alkyl groups, thealkoxy groups and the halogen atoms are the same as those mentionedabove, and the substituted amino groups are the same as those to bedescribed below, and the alkyl groups substituted with halogen atoms,namely the halogenated alkyl groups are the same as those describedabove.

The substituents in the substituted alkenyl groups (for example, thesubstituted vinyl groups) and substituted alkynyl groups (for example,the substituted propargyl groups) can also be the same as thosementioned above.

The substituted aryl groups include the aryl groups as mentioned above,at least one of the hydrogen atoms of which are substituted with asubstituent such as alkyl groups, halogenated hydrocarbon groups, alkoxygroups, halogen atoms, amino groups, substituted amino groups, etc., andalso the aryl groups, two adjacent hydrogen atoms of which are replacedby substituents such as alkylenedioxy groups, etc., wherein the alkylgroups, the halogenated hydrocarbon groups, the alkoxy groups, thehalogen atoms, and the substituted amino groups are the same asmentioned above, and the substituted amino groups are the same asdescribed below. Specific examples of the aryl groups substituted withalkyl groups include a tolyl group and a xylyl group. The alkylenedioxygroups can be alkylenedioxy groups of 1 to 3 carbon atoms. Specificexamples of the alkylenedioxy groups include methylenedioxy,ethylenedioxy, propylenedioxy, trimethylenedioxy, etc.

The substituted aralkyl groups include those mentioned above, at leastone of the hydrogen atoms of which are substituted with a substituentsuch as alkyl groups, halogenated hydrocarbon groups, alkoxy groups,halogen atoms, amino groups, substituted amino groups, etc., and thearalkyl groups, two adjacent hydrogen atoms on the aryl group of whichare replaced with substituents such as alkylenedioxy groups, etc.,wherein the alkyl groups, the halogenated hydrocarbon groups, the alkoxygroups, the halogen atoms, and the substituted amino groups are the sameas mentioned above, and the substituted amino groups are the same asdescribed below.

The substituted aliphatic heterocyclic groups include those mentionedabove, at least one of the hydrogen atoms of which is substituted with asubstituent such as alkyl groups, halogenated hydrocarbon groups, alkoxygroups, halogen atoms, etc., wherein the alkyl groups, the halogenatedhydrocarbon groups, the alkoxy groups and the halogen atoms are the sameas mentioned above.

The substituted aromatic heterocyclic groups include those mentionedabove, at least one of the hydrogen atoms of which are substituted witha substituent such as alkyl groups, halogenated hydrocarbon groups,alkoxy groups, halogen atoms, etc., wherein the alkyl groups, thehalogenated hydrocarbon groups, the alkoxy groups, and the halogen atomsare the same as mentioned above.

The substituted alkoxy groups include those mentioned above, at leastone of the hydrogen atoms of which are substituted with a substituentsuch as alkyl groups, halogenated hydrocarbon groups, alkoxy groups,halogen atoms, amino groups, substituted amino groups, etc., wherein thealkyl groups, the halogenated hydrocarbon groups, the alkoxy groups, andthe halogen atoms and the substituted amino groups are the same asmentioned above and the substituted amino groups are the same asdescribed below.

The substituted aryloxy groups include those mentioned above, at leastone of the hydrogen atoms of which are substituted with a substituentsuch as alkyl groups, halogenated hydrocarbon groups, alkoxy groups,halogen atoms, amino groups and substituted amino groups, and thearyloxy groups, two adjacent hydrogen atoms on the aryl group of whichare replaced by substituents such as an alkylenedioxy group, etc.,wherein the alkyl groups, the halogenated hydrocarbon groups, the alkoxygroups, the halogen atoms, and the substituted amino groups and thealkylenedioxy groups are the same as mentioned above, and thesubstituted amino groups are the same as described below.

The substituted aralkyloxy groups include the same aralkyloxy groups asmentioned above, at least one of the hydrogen atoms of which aresubstituted with a substituent such as alkyl groups, halogenatedhydrocarbon groups, alkoxy groups, halogen atoms, the amino groups andsubstituted amino groups, and aralkyloxy groups, two adjacent hydrogenatoms on the aryl group of which are replaced by substituents such asalkylenedioxy groups, etc., wherein the alkyl groups, the halogenatedhydrocarbon groups, the alkoxy groups, the halogen atoms, thesubstituted amino groups and the alkylenedioxy groups are the same asthose mentioned above, and the substituted amino groups are the same asthe substituted amino groups described below.

The substituted amino groups include amino groups of which one or twohydrogen atoms are substituted with substituents such as protectivegroups, etc. Any protective groups can be used so long as they are usedas amino protecting groups, and may be selected from those described inPROTECTIVE GROUPS IN ORGANIC SYNTHESIS Second Edition (JOHN WILEY &SONS, INC) as amino protecting groups. Specific examples of the aminoprotecting groups include an alkyl group, an aryl group, an aralkylgroup, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group,an aralkyloxycarbonyl group, etc., wherein the alkyl, aryl, aralkyl,acyl, alkoxycarbonyl, aryloxycarbonyl and aralkyloxycarbonyl groups arethe same as those mentioned above.

Specific examples of the amino groups substituted with alkyl group(s),namely alkyl-substituted amino groups, include mono- or dialkylaminogroups, such as N-methylamino, N,N-dimethylamino, N,N-diethylamino,N,N-diisopropylamino, N-cyclohexylamino, etc. Specific examples of theamino groups substituted with aryl group(s), namely aryl-substitutedamino groups, include mono- or diarylamino groups, such asN-phenylamino, N,N-diphenylamino, N-naphthylamino,N-naphthyl-N-phenylamino, etc. Specific examples of the amino groupssubstituted with aralkyl group(s), namely aralkyl-substituted aminogroups, include mono- or diaralkylamino groups, such as N-benzylamino,N,N-dibenzylamino, etc. Specific examples of the amino groupssubstituted with acyl group(s), namely acylamino groups, includeformylamino, acetylamino, propionylamino, pivaloylamino, pentanoylamino,hexanoylamino, and benzoylamino, etc. Specific examples of the aminogroups substituted with alkoxycarbonyl group(s), namelyalkoxycarbonylamino groups, include methoxycarbonylamino,ethoxycarbonylamino, n-propoxycarbonylamino, n-butoxycarbonylamino,tert-butoxycarbonylamino, pentyloxycarbonylamino, hexyloxycarbonylamino,etc. Specific examples of the amino groups substituted witharyloxycarbonyl group(s), namely aryloxycarbonylamino groups, includeamino groups, one of the hydrogen atoms of which is substituted with anaryloxycarbonyl group mentioned above, e.g., more specifically,phenoxycarbonylamino, and naphthyloxycarbonylamino groups. Specificexamples of the amino groups substituted with an aralkyloxycarbonylgroup, namely aralkyloxycarbonylamino groups, includebenzyloxycarbonylamino group, etc.

Here, the groups preferable as R³ to R⁷ are hydrocarbon groups, halogenatoms or halogenated hydrocarbon groups, and at least one of R³ to R⁷ isa halogen atom or a halogenated hydrocarbon group, and either R³ or R⁷is a hydrogen atom.

Specific examples of β-ketoesters (hereinafter called as β-ketoesters(2)) of formula (2) include the following compounds:

β-ketoesters (2) such as

methyl 3-oxopentanoate,

t-butyl 3-oxopentanoate,

ethyl 3-oxopentanoate,

isopropyl 3-oxopentanoate,

benzyl 3-oxopentanoate,

methyl 5-methyl-3-oxohexanoate,

methyl 3-oxobutyrate,

ethyl 3-oxobutyrate,

methyl 3-oxo-4-phenylbutyrate,

methyl 5,5-dimethyl-3-oxohexanoate, etc.,

dimethyl 2-oxosuccinate,

diethyl 2-oxosuccinate, and

dimethyl 3-oxopentandioate.

In the formula (2), a hydrocarbon group of R¹ is preferable, and analkyl group is more preferable. Also, a hydrocarbon group of R² ispreferable, and an alkyl group is more preferable. These R¹ and R² areapplied to formulae below.

Specific examples of the amines of formula (3) (hereinafter called asamine (3)) include 4-trifluoromethylaniline, 3-trifluoromethylaniline,2-trifluoromethylaniline, 3,5-bis(trifluoromethyl)aniline,2,5-bis(trifluoromethyl)aniline, 3,4,5-tris(trifluoromethyl)aniline,4-fluoroaniline, 3-fluoroaniline, 2-fluoroaniline, 3,4-difluoroaniline,2,4-difluoroaniline, 2,3-difluoroaniline, 3,5-difluroaniline,2,3,4-trifluoroaniline, 2,4,5-trifluoroaniline, 4-chloroaniline,3-chloroaniline, 2-chloroaniline, 3,4-dichloroaniline,3,5-dichloroaniline, 2,3,4-trichloroaniline, 2,4,5-trichloroaniline,3,4,5-trichloroaniline, 4-bromoaniline, 3-bromoaniline, 2-bromoaniline,2,4-dibromoaniline, 2,5-dibromoaniline, 3,4,5-tribromoaniline,4-iodoaniline, 3-iodoaniline, 2-iodoaniline, 4-methoxyaniline,3-methoxyaniline, 2-methoxyaniline, etc.

In the formula (3), R³ is preferably a hydrogen atom; and at least oneof R⁴ to R⁷ is preferably a hydrogen atom, an alkoxy group, ahalogenated hydrocarbon group or a halogen atom; among above, morepreferably (a) R⁵ is an alkoxy group or a halogenated hydrocarbon group,or (b) at least one of R⁴ to R⁶ is a halogen atom and other R⁴ to R⁶ andR⁷ are each a hydrogen atom; further preferably (c) R⁵ is an alkoxygroup or a halogenated hydrocarbon group, and R⁴, R⁶, R⁷ are each ahydrogen atom, or (d) R⁴, R⁶ are each a halogen atom and R⁵, R⁷ are eacha hydrogen atom; furthermore preferably (e) R⁵ is a methoxy or afluorine-containing alkyl group of 1 to 3 carbon atoms, and R⁴, R⁶, R⁷are each a hydrogen atom, or (f) R⁴, R⁶ are each a chlorine atom and R⁵,R⁷ are each a hydrogen atom; the most preferably, R⁵ is atrifluoromethyl and R⁴, R⁶, R⁷ are each a hydrogen atom. These R³ to R⁷are applied to formulae below.

Specific examples of enaminoesters of formula (4) (hereinafter called asenaminoesters (4)) include the following compounds:

Among enaminoesters (4) obtained above, the enaminoesters of formula (9)below are used preferably:

wherein R¹⁰ is a hydrocarbon group a substituted hydrocarbon group orCOOR¹⁶ (R¹⁶ is a hydrocarbon group or a substituted hydrocarbon group);R¹¹ is a hydrocarbon group or a substituted hydrocarbon group; R¹² toR¹⁵ are each independently a hydrogen atom, a hydrocarbon group, analkoxy group, a halogen atom or a halogenated hydrocarbon group, withthe proviso that (1) when at least one of R¹² to R¹⁵ is a halogen atomor a halogenated hydrocarbon group, and at least one of R¹² to R¹⁵ isCF₃ or a bromine atom, then R¹⁰ is a hydrocarbon group except formethyl, and that (2) when at least one of R¹² to R¹⁵ is a halogen atom,then R¹⁰ is a hydrocarbon group except for methyl.

The hydrocarbon group, halogen atom and halogenated hydrocarbon groupare each the same as described above.

Furthermore, of the enaminoesters, enaminoesters of formula (9), whereinat least one of R¹² to R¹⁵ is a hydrogen atom, an alkoxy group, ahalogenated hydrocarbon group or a halogen atom, is preferable.

Among them, of those wherein (a) at least one of R¹² to R¹⁴ is a halogenatom and other R¹² to R¹⁴ and R¹⁵ are each a hydrogen atom, or (b) R¹³is an alkoxy group or a halogenated hydrocarbon group, are preferable;and of those, wherein (c) R¹³ is an alkoxy group or a halogenatedhydrocarbon group, and R¹², R¹⁴, R¹⁵ are each a hydrogen atom, or (d)R¹², R¹⁴ are each a halogen atom and R¹³, R¹⁵ are each a hydrogen atom,are more preferable.

Among them, of those wherein (e) R¹³ is methoxy or a fluorine-containingalkyl group of 1 to 3 carbon atoms and R¹², R¹⁴, R¹⁵ are each a hydrogenatom, or (f) R¹², R¹⁴ are each a chlorine atom and R¹³, R¹⁵ are each ahydrogen atom, are further preferable; and of those, wherein R¹³ istrifluoromethyl and R¹², R¹⁴, R¹⁵ are each a hydrogen atom is mostpreferable.

Further, R¹⁰ of hydrocarbon group is preferable with the proviso that(1) when at least one of R¹² to R¹⁵ is a halogen atom or a halogenatedhydrocarbon group, and at least one of R¹² to R¹⁵ is CF₃ or a bromineatom, then R¹⁰ is a hydrocarbon group except for methyl, and that (2)when at least one of R¹² to R¹⁵ is a halogen atom, then R¹⁰ is ahydrocarbon group except for methyl, an alkyl group is more preferablewith the proviso that (1) when at least one of R¹² to R¹⁵ is a halogenatom or a halogenated hydrocarbon group, and at least one of R¹² to R¹⁵is CF₃ or a bromine atom, then R¹⁰ is a hydrocarbon group except formethyl, and that (2) when at least one of R¹² to R¹⁵ is a halogen atom,then R¹⁰ is a hydrocarbon group except for methyl, and ethyl is mostpreferable.

Furthermore, R¹¹ of hydrocarbon group is preferable, an alkyl group ismore preferable, and methyl is most preferable.

Specific examples of the optically active β-amino acid derivatives offormula (5) (hereinafter called as β-amino acid derivatives (5))include, for example compounds as follows:

As to the optically active β-amino acid derivatives (5) obtained by theasymmetric hydrogenation, the β-amino acid derivatives of formula (15c)above are preferably obtained. Among those β-amino acid derivatives,optically active β-amino acid derivatives of formula (15),

wherein * indicates an asymmetric carbon atom; R²⁵ to R³¹ have the samemeanings as mentioned above, are obtained more preferably, and opticallyactive β-amino acid derivatives of formula (15a) and formula (15b),

wherein R²⁵, R²⁶ and R²⁸ to R³¹ have the same meanings as mentionedabove, are obtained especially preferably.

Further, in formulae (15) and (15c), R²⁷ of a hydrogen atom ispreferable.

Furthermore, of the β-amino acid derivatives of formulae (15), (15a),(15b) and (15c), wherein at least one of R²⁸ to R³¹ is a hydrogen atom,an alkoxy group, a halogenated hydrocarbon group or a halogen atom, ispreferable with the proviso that either i) R²⁷ or R³¹ is a hydrogenatom, ii) at least one of R²⁷ to R³¹ is a hydrocarbon group, a halogenatom, a halogenated hydrocarbon group or an alkoxy group, iii) when atleast one of R²⁷ to R³¹ is an alkoxy group, R²⁵ is a methyl group or anethyl group, and iv) when at least one of R²⁷ to R³¹ is a halogen atomor a methyl group, R²⁵ is a hydrocarbon group.

Among them, of those wherein (a) at least one of R²⁸ to R³⁰ is a halogenatom and other R²⁸ to R³⁰ and R³¹ are each a hydrogen atom, or (b) R²⁹is an alkoxy group or a halogenated hydrocarbon group, are preferable;and of those, wherein (c) R²⁹ is an alkoxy group or a halogenatedhydrocarbon group and R²⁸, R³⁰, R³¹ are each a hydrogen atom, or (d)R²⁸, R³⁰ are each a halogen atom and R²⁹, R³¹ are each a hydrogen atom,are more preferable.

Among them, of those wherein (e) R²⁹ is methoxy or a fluorine-containingalkyl group of 1 to 3 carbon atoms and R²⁸, R³⁰, R³¹ are each a hydrogenatom, or (f) R²⁸, R³⁰ are each a chlorine atom and R²⁹, R³¹ are each ahydrogen atom, are further preferable; and of those, wherein R²⁹ istrifluoromethyl and R²⁸, R³⁰, R³¹ are each a hydrogen atom is the mostpreferable.

Further, R²⁵ of hydrocarbon group is preferable, an alkyl group is morepreferable, and ethyl is the most preferable.

Furthermore, R²⁶ of hydrocarbon group is preferable, an alkyl group ismore preferable, and methyl is the most preferable.

In formulae (15), (15a), (15b) and (15c), the hydrocarbon groups,halogen atoms and halogenated hydrocarbon groups have the same meaningsas mentioned above.

Specific examples of the optically active amides of formula (6) above(hereinafter called optically active amides (6)) include the followingcompounds:

The optically active amides (6) obtained by the amidation are opticallyactive amides (16a) below, when optically active β-amino acidderivatives (15a) above are used, and the optically active amides (6)obtained by the aimidation are optically active amides (16b) below, whenthe optically active β-amino acid derivatives (15b) above are used,

wherein R¹ and R⁴ to R⁷ have the same meanings as mentioned above.

The compounds (7) above obtained by the alkoxycarbonylation of theamides (6) are optically active compounds (17a) below, when amides offormula (16a) above are used, and the compounds (7) are optically activecompounds (17b) below, when amides of formula (16b) above are used.

wherein R¹ and R⁴ to R⁸ have the same meanings as mentioned above.

Specific examples of the compounds of formula (7) above (hereinaftercalled compounds (7)) include the following compounds:

Specific examples of the optically active tetrahydroquinolines offormula (1) above (hereinafter called optically activetetrahydroquinolines (1)) include the following compounds:

In the method for producing optically active tetrahydroquinolines (1) ofthe present invention, β-ketoesters (2) and amines (3) are first made toreact in the presence of an acid to give enaminoesters (4).

The amount used of β-ketoesters (2) is usually selected appropriatelyfrom the range of 0.7 to 2.0 equivalents, preferably of 0.8 to 1.5equivalents, to the amount used of amines (3).

Various acidic substances such as inorganic acids, organic acids andLewis acids can be used as the said acid. Examples of the inorganicacids include hydrochloric acid, sulfuric acid, phosphoric acid,polyphosphoric acid. Examples of the organic acids include carboxylicacids such as formic acid, acetic acid, chloroacetic acid,dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, etc.;sulfonic acids such as benzenesulfonic acid, para-toluenesulfonic acid,methanesulfonic acid, camphorsulfonic acid, etc.; solid acids such asion-exchange resins having functional groups such as sulfo, carboxyl,etc. Examples of the Lewis acids include titanium tetrachloride, borontrifluoride etherate, zinc chloride, scandium triflate, lanthanumtriflate, tri(tert-butyl)borate. Among these acids, acetic acid,para-toluenesulfonic acid, boron trifluoride etherate, and solid acidsare preferable.

The amount used of the acid can be usually selected appropriately fromthe range of 0.01 to 0.3 equivalent, or preferably of 0.01 to 0.2equivalent to the amount of the amine used.

The reaction of β-ketoester (2) with amine (3) is preferably carried outin the presence of a solvent. Examples of the solvent include aliphatichydrocarbons such as pentane, hexane, heptane, octane, decane,cyclohexane, etc; aromatic hydrocarbons such as benzene, toluene,xylene, etc.; halogenated hydrocarbons such as dichloromethane,1,2-dichloroethane, chloroform, carbon tetrachloride, o-dichlorobenzene,etc.; ethers such as diethyl ether, diisopropyl ether, tert-butyl methylether, dimethoxyethane, ethyleneglycol diethyl ether, tetrahydrofuran,1,4-dioxane, 1,3-dioxolane, etc.; alcohols such as methanol, ethanol,2-propanol, 1-butanol, 2-ethoxyethanol, benzyl alcohol, etc.;polyalcohols such as ethylene glycol, propylene glycol, 1,2-propanediol,glycerol, etc.; esters such as methyl acetate, ethyl acetate, n-butylacetate, methyl propionate, etc.; amides such as formamide,N,N-dimethylformamide, N,N-dimethylacetamide, etc.; sulfoxides such asdimethyl sulfoxide, etc.; cyano-containing organic compounds such asacetonitrile, etc.; N-methylpyrolidone, and water.

These solvents may be used solely, or in optional combination of two ormore solvents thereof.

The amount used of the solvent is appropriately selected usually fromthe range of 1 to 15 times, or more preferably from the range of 1 to 10times the volume of amines (3).

The reaction temperature is appropriately selected usually from therange of 0 to 140° C., or more preferably from the range of 20 to 120°C.

The reaction time is appropriately selected usually from the range of 1to 12 hours, or more preferably from the range of 1 to 10 hours.

Enaminoesters (4) obtained above are then subjected to asymmetrichydrogenation to produce optically active β-amino acid derivatives (5)above.

The asymmetric hydrogenation gives optically active β-amino acidderivatives (5) efficiently and in excellent asymmetric yields when itis carried out in the presence of asymmetric hydrogenation catalysts.

Transition metal complexes can be preferably used as the asymmetriccatalysts for the asymmetric hydrogenation, and, among those transitionmetal complexes, those of group 8, 9, 10 metals in the periodic table ofelements are preferably used.

Examples of the transition metal complexes include compounds of formula12 and formula 13,M_(m)L_(n)X_(p)Y_(q)  (12)M_(m)L_(n)X_(p)Y_(q)]Z_(s)  (13)wherein M is a transition metal of group VIII in the periodic table ofelements; L is a chiral ligand; X is a halogen atom, a carboxylatogroup, an allyl group, a 1,5-cyclooctadiene or a norbornadiene; Y is aligand; Z is an anion; and m, n, p, q and s are each an integer of 0 to5.

In formulae (12) and (13), the Ms, the group 8, 9, 10 transition metalsin the periodic table of elements, are the same or different, andinclude ruthenium (Ru), rhodium (Rh), iridium (Ir), palladium (Pd),nickel (Ni), etc.

The chiral ligands represented by L are the same or different, andinclude monodentate ligands, bidentate ligands, etc. The opticallyactive phosphine ligands are preferable, and the optically activebidentate phosphine ligands are more preferable as the chiral ligands.

Examples of the optically active bidentate phosphine ligands includephosphine compounds of formula (20),R^(a)R^(b)P-Q-PR^(c)R^(d)  (20)wherein R^(a) to R^(d) are each independently an alkyl group, asubstituted alkyl group, an aryl group, a substituted aryl group, aheterocyclic group or a substituted heterocyclic group; Q is a spacer.

The alkyl groups, substituted alkyl groups, aryl groups and substitutedaryl groups represented by R^(a) to R^(d) can have the same meanings asthose described above, and R^(a) and R^(b) and/or R^(c) and R^(d), takentogether, may form a ring.

The heterocyclic groups include aliphatic heterocyclic groups andaromatic heterocyclic groups, and the substituted heterocyclic groupsinclude substituted aliphatic heterocyclic groups and substitutedaromatic heterocyclic groups. These aliphatic heterocyclic groups,aromatic heterocyclic groups, substituted aliphatic heterocyclic groupsand substituted aromatic heterocyclic groups can have the same meaningsas those described above.

The spacers represented by Q include divalent organic groups such asalkylene groups and arylene groups, etc. which may be substituted.

Examples of the alkylene groups include alkylene groups of 1 to 6 carbonatoms, and specific examples of them include methylene, ethylene,trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene,etc. Examples of the arylene groups include arylene groups of 6 to 20carbon atoms, and specific examples of them include phenylene,biphenyldiyl, binaphthalenediyl, etc. These divalent organic groups maybe substituted with substituents such as alkyl groups, aryl groups,heterocyclic groups and alkylenedioxy groups, all of which are the sameas described above.

The spacer represented by Q could be an optically active spacer. In caseof ethylene group as the spacer which has no asymmetric carbon atom, atleast one of the hydrogen atom in the spacer is substituted by asubstituent such as phenyl group to form an optically active spacer.

Specific examples of the chiral ligands includecyclohexylanisylmethylphosphine(CAMP),1,2-bis(anisylphenylphosphino)ethane(DIPAMP),1,2-bis(alkylmethylphosphino)ethane(Bis P*),2,3-bis(diphenylphosphino)butane(CHIRAPHOS),1,2-bis(diphenylphosphino)propane(PROPHOS),2,3-bis(diphenylphosphino)-5-norbornene(NORPHOS),2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane(DIOP),1-cyclohexyl-1,2-bis(diphenylphosphino)ethane(CYCPHOS),1-substituted-3,4-bis(diphenylphosphino)pyrrolidine(DEGPHOS),2,4-bis(diphenylphosphino)pentane(SKEWPHOS),1,2-bis(substituted-phospholano)benzene(DuPHOS),1,2-bis(substituted-phospholano)ethane(BPE),1-((substituted-phospholano)-2-(diphenylphosphino)benzene(UCAP-Ph),1-(bis(3,5-dimethylphenyl)phosphino)-2-(substituted-phospholano)benzene(UCAP-DM),1-((substituted-phospholano)-2-(bis(3,5-di(t-butyl)-4-methoxyphenyl)phosphino)benzene(UCAP-DTBM),1-((substituted-phospholano)-2-(di-naphthalen-1-ylphosphino)benzene(UCAP-(1-Nap)),1-[1′,2-bis(diphenylphosphino)ferrocenyl]ethylamine(BPPFA),1-[1′,2-bis(diphenylphosphino)ferrocenyl]ethyl alcohol(BPPFOH),2,2′-bis(diphenylphosphino)-1,1′-dicyclopentane(BICP),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(BINAP),2,2′-bis(diphenylphosphino)-1,1′-(5,5′,6,6′,7,7′,8,8′-octahydrobinaphthyl)(H₈-BINAP),2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl(TOL-BINAP),2,2′-bis(di(3,5-dimethylphenyl)phosphino)-1,1′-binaphthyl(DM-BINAP),2,2′-bis(diphenylphosphino)-6,6′-dimethyl-1,1′-biphenyl(BICHEP),((5,6),(5′,6′)-bis(methylenedioxy)biphenyl-2,2′-diyl)(bisdiphenylphosphine)(SEGPHOS),((5,6),(5′,6′)-bis(methylenedioxy)biphenyl-2,2′-diyl)(bis(3,5-dimethylphenyl)phosphine)(DM-SEGPHOS)and((5,6),(5′,6′)-bis(methylenedioxy)biphenyl-2,2′-diyl)(bis(3,5-di(tert-butyl)-4-methoxyphenyl)phosphine)(DTBM-SEGPHOS).

The word “substituted” above includes any groups as far as they do notinhibit the reaction of the present invention. Chiral ligands describedabove with further substituents can also be appropriately used.

The ligands represented by Y are the same or different and includeneutral ligands such as aromatic compounds and olefinic compounds.Examples of the aromatic compounds include benzene, p-cymene,1,3,5-trimethylbenzene(mesitylene) and hexamethylbenzene. Examples ofthe olefinc compounds include ethylene, 1,5-cyclooctadiene,cyclopentadiene and norbornadiene. Examples of the other neutral ligandsinclude N,N-dimethylformamide (DMF), acetonitrle, benzonitrile, acetoneand chloroform.

The halogen atoms represented by X include a chlorine atom, a bromineatom and an iodine atom.

The anions represented by Z in formula (13) include BF₄, ClO₄, OTf, PF₆,SbF₆, BPh₄, Cl, Br, I, I₃ and sulfonate, wherein Tf represents atriflate group (SO₂CF₃).

The following is the description of the preferable embodiments of thetransition metal complexes mentioned above.

[1] As to Formula (12):M_(m)L_(n)X_(p)Y_(q)  (12)

-   1) When M is Ir or Rh, X is then Cl, Br or I, and when L is a    monodentate ligand, then m=p=2, n=4 and q=0; and when L is a    bidentate ligand, then m=n=p=2 and q=0.-   2) When M is Ru, then (i) X is Cl, Br or I, and Y is a trialkylamino    group, and when L is a monodentate ligand, then m=2, n=p=4 and q=1;    and when L is a bidentate ligand, then m=n=2, p=4, and q=1, or

(ii) X is Cl, Br, or I, and Y is a pyridyl group or a pyridyl groupsubstituted on the ring, and when L is a monodentate ligand, then m=1,n=p=2 and q=2; and when L is a bidentate ligand, then m=n=1, p=2 andq=2, or

(iii) X is a carboxylato group, and when L is a monodentate ligand, thenm=1, n=p=2 and q=0; and when L is a bidentate ligand, m=n=1, p=2 andq=0.

(iv) X is Cl, Br or I, and when L is a monodentate ligand, then m=p=2,n=4 and q=0; and when L is a bidentate ligand, then m=n=p=2 and q=0.

-   3) When M is Pd, (i) X is Cl, Br or I, and when L is a monodentate    ligand, then m=1, n=2, p=2 and q=0; and when L is a bidentate    ligand, m=n=1, p=2 and q=0, or

(ii) X is an allyl group, and when L is a monodentate ligand, thenm=p=2, n=4 and q=0; and when L is a bidentate ligand, then m=n=p=2 andq=0.

-   4) When M is Ni, X is then Cl, Br or I, and when L is a monodentate    ligand, then m=1, n=2, p=2 and q=0; and when L is a bidentate    ligand, then m=n=1, p=2 and q=0.    [2] As to Formula (13):    [M_(m)L_(n)X_(p)Y_(q)]Z_(s)  (13)-   1) When M is Ir or Rh, then X is 1,5-cyclooctadiene or    norbornadiene, and Z is BF₄, ClO₄, OTf, PF₆, SbF₆ or BPh₄, and    m=n=p=s=l and q=0, or m=s=1, n=2 and p=q=0.-   2) When M is Ru, then (i) X is Cl, Br or I, Y is a neutral ligand    such as an aromatic compound and an olefinic compound, Z is Cl, Br,    I, I₃ or sulfonate, and when L is a monodentate ligand, then    m=p=s=q=1 and n=2; and when L is a bidentate ligand, then    m=n=p=s=q=1, or

(ii) X is Cl, Br or I, Z is BF₄, ClO₄, OTf, PF₆, SbF₆ or BPh₄, and whenL is a monodentate ligand, then m=1, n=2, p=q=0 and s=2; and L is abidentate ligand, then m=n=1, p=q=0 and s=2.

-   3) When M is Pd or Ni, then (i) Z is BF₄, ClO₄, OTf, PF₆, SbF₆ or    BPh₄, and when L is a monodentate ligand, then m=1, n=2, p=q=0 and    s=2; and when L is a bidentate ligand, then m=n=1, p=q=0 and s=2.

These transition metal complexes can be produced by using the knownmethods.

In addition, symbols used in the formulae of transition metal complexesbelow have the meanings as follows: L: a chiral ligand; cod:1,5-cyclooctadiene; nbd: norbornadiene; Tf: a triflate group (SO₂CF₃);Ph: a phenyl group, and Ac: an acetyl group. Specific examples of thetransition metal complexes are given below, although only those whichhave bidentate ligands as the chiral ligand are selected to avoid toomuch complexity for the explanation.

Rhodium Complexes:

Rhodium complexes can be produced by the methods described in JikkenKagaku Kouza, 4^(th) Ed., Vol. 18, Organic Metal Complexes, p. 339-344(1991)(Edited by Nihon Kagakukai) (Maruzen), etc. or, more specifically,by reacting bis(cycloocta-1,5-diene)rhodium(I) tetrafluoroborate with achiral ligand.

Specific examples of the rhodium complexes include those as follows:

[Rh(L)Cl]₂, [Rh(L)Br]₂, [Rh(L)I]₂, [Rh(cod)(L)]BF₄, [Rh(cod)(L)]ClO₄,[Rh(cod)(L)]PF₆, [Rh(cod)(L)]BPh₄, [Rh(cod)(L)]OTf, [Rh(nbd)(L)]BF₄,[Rh(nbd)(L)]ClO₄, [Rh(nbd)(L)]PF₆, [Rh(nbd)(L)]BPh₄, [Rh(nbd)(L)]OTf and[Rh(L)₂]ClO₄.

Ruthenium Complexes:

Ruthenium complexes can be produced by the methods described in theliterature: T. Ikariya, Y. Ishii, H. Kawano, T. Arai, M. Saburi, S.Yoshikawa, and S. Akutagawa, J. Chem. Soc., Chem. Commun., 1985, 922,etc. More specifically, they can be produced by heating [Ru(cod)Cl₂]_(n)and a chiral ligand in toluene under reflux in the presence oftriethylamine.

They can also be produced by the method described in the literature: K.Mashima, K. Kusano, T. Ohta, R. Noyori, H. Takaya, J. Chem. Soc., Chem.Commun., 1989, 1208. More specifically, they can be produced by heating[Ru(p-cymene)I₂]₂ and a chiral ligand in methylene chloride and ethanolunder reflux with stirring.

Specific examples of the ruthenium complexes include those as follows:Ru(OAc)₂(L), Ru₂Cl₄(L)₂NEt₃, [RuCl(benzene)(L)]Cl, [RuBr(benzene)(L)]Br,[RuI(benzene)(L)]I, [RuCl(p-cymene)(L)]Cl, [RuBr(p-cymene)(L)]Br,[RuI(p-cymene)(L)]I, [Ru(L)](BF₄)₂, [Ru(L)](ClO₄)₂, [Ru(L)](PF₆)₂,[Ru(L)](BPh₄)₂, [Ru(L)](OTf)₂, Ru(OCOCF₃)₂(L),[{RuCl(L)}₂(μ-Cl)₃][Me₂NH₂] and [{RuCl(L)}₂(μ-Cl)₃][Et₂NH₂].

Iridium Complexes:

Iridium complexes can be produced by the methods described in theliterature: K. Mashima, T. Akutagawa, X. Zhang, T. Taketomi, H.Kumobayashi, S. Akutagawa, J. Organomet. Chem., 1992, 428, 213), etc.More specifically, they can be produced by reacting a chiral ligand with[Ir(cod)(CH₃CN)₂]BF₄ in tetrahydrofuran with stirring.

Specific examples of the iridium complexes include those as follows:[Ir(L)Cl]₂, [Ir(L)Br]₂, [Ir(L)I]₂, [Ir(cod)(L)]BF₄, [Ir(cod)(L)]ClO₄,[Ir(cod)(L)]PF₆, [Ir(cod)(L)]BPh₄, [Ir(cod)(L)]OTf, [Ir(nbd)(L)]BF₄,[Ir(nbd)(L)]ClO₄, [Ir(nbd)(L)]PF₆, [Ir(nbd)(L)]BPh₄ and [Ir(nbd)(L)]OTf.

Palladium Complexes:

Palladium complexes can be produced by the methods described in theliterature: Y. Uozumi and T. Hayashi: J. Am. Chem. Soc., 1991, 9887,etc. More specifically, they can be produced by reacting a chiral ligandwith π-allyl-palladium chloride.

Specific examples of the palladium complexes include those as follows:PdCl₂(L), (π-allyl)Pd(L), [Pd(L)]BF₄, [Pd(L)]ClO₄, [Pd(L)]PF₆,[Pd(L)]BPh₄ and [Pd(L)]OTf.

Nickel Complexes:

Nickel complexes can be produced by the methods described in JikkenKagaku Kouza, 4^(th) Ed., Vol. 18, Organic Metal Complexes, p. 376(1991)(Edited by Nihon Kagakukai)(Maruzen), etc. They can also beobtained, according to the method described in the literature: Y. Uozumiand T. Hayashi, J. Am. Chem. Soc., 1991, 113, 9887, by dissolving achiral ligand and nickel chloride in a mixed solvent of 2-propanol andmethanol, followed by heating with stirring.

Specific examples of the nickel complexes include those as follows:NiCl₂(L), NiBr₂(L) and NiI₂(L).

As to the transition metal complexes mentioned above, both the onescommercially available and the ones obtained by preparation may beemployed.

In addition, those complexes which prepared in situ may also be appliedto the asymmetric hydrogenation.

Among the transition metal complexes used in the present invention,those having chiral ligands are used preferably, and those having chiralphosphine ligands as the said chiral ligands are used more preferably.

In the production method of the present invention, the amount used ofthe asymmetric hydrogenation catalyst mentioned above is appropriatelyselected usually from the range of 1/10 to 1/100,000 times, orpreferably from the range of 1/50 to 1/10,000 times, that ofenaminoesters (4) in moles, depending on the enaminoesters (4) used, thereaction vessel used, and the mode or economy of the reaction.

The asymmetric hydrogenation can be carried out, as required, in asolvent. For the said solvent, those which dissolve both theenaminoesters (4) and the asymmetric hydrogenation catalysts arepreferable.

Examples of the solvent include aliphatic hydrocarbons such as pentane,hexane, heptane, octane, decane, cyclohexane, etc.; aromatichydrocarbons such as benzene, toluene, xylene, etc.; halogenatedhydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform,carbon tetrachloride, o-dichlorobenzene, etc.; ethers such as diethylether, diisopropyl ether, tert-butyl methyl ether, dimethoxyethane,ethyleneglycol diethyl ether, tetrahydrofuran, 1,4-dioxane,1,3-dioxolane, etc.; alcohols such as methanol, ethanol, 2-propanol,1-butanol, 2-butanol, tert-butanol, 2-ethoxyethanol, benzyl alcohol,etc.; polyalcohols such as ethylene glycol, propylene glycol,1,2-propanediol, glycerol, etc.; amides such as N,N-dimethylformamide,N,N-dimethylacetamide, etc.; sulfoxides such as dimethyl sulfoxide,etc.; cyano-containing organic compounds such as acetonitrile, etc.;N-methylpyrrolidone; and water. These solvents may be used solely or inoptional combination of two or more solvents thereof. Among thesesolvents, alcohols such as methanol, ethanol, 2-propanol, 1-butanol,2-butanol, tert-butanol, 2-ethoxyethanol, benzyl alcohol, etc. arepreferable.

The amount of the solvent used is determined considering the solubilityof the enaminoesters (4) to be used and cost effectiveness. When, forexample, an alcohol is used as solvent, the reaction can be carried out,with some enaminoesters (4), in concentrations ranging from less than 1%to without or almost without solvent. The amount of the solvent used isappropriately selected usually from the range of 0.1 to 10 times, ormore preferably from 0.5 to 5 times, the volume of the enaminoesters (4)used.

Although atmospheric hydrogen or 1 atmosphere (atmospheric pressure)(0.1 MPa) of hydrogen is enough for the asymmetric hydrogenation, thepressure of hydrogen is appropriately selected usually from the range of1 to 200 atm. (0.1 to 20 MPa), or more preferably of 2 to 100 atm. (0.2to 10 MPa), considering cost effectiveness, etc. It is also possible tomaintain a high activity under pressure of not higher than 10 atm. (1MPa), considering cost effectiveness.

The reaction temperature is appropriately selected usually from therange of 15 to 120° C., or more preferably from the range of 20 to 100°C., considering cost effectiveness, etc. However, the reaction itselfcan be carried out at temperatures as low as from −30 to 0° C., or attemperatures as high as 100 to 250° C.

Although the reaction time varies with the reaction conditions, etc.such as the kind and amount used of the asymmetric hydrogenationcatalysts, kind and concentration used of the enaminoesters (4),reaction temperature and pressure of hydrogen, etc., the reaction iscompleted in a time from several minutes to several hours. The reactiontime is selected usually from the range of 1 minute to 48 hours, or morepreferably from the range of 10 minutes to 24 hours.

The asymmetric hydrogenation can be carried out both in a batch processand in a continuous process.

The optical purity of the optically active β-amino acid derivatives (5)obtained by the production method of the present invention is equal toor higher than 85% e.e., preferably 90% e.e.

In the amidation, the optically active amides (6) are obtained byreacting the optically active β-amino acid derivatives (5) obtained withammonia or ammonium salts.

Examples of such ammonium salts include ammonium salt such as ammoniumacetate, ammonium formate, ammonium phosphate, ammonium chloride,ammonium sulfate, etc.

The amount of the ammonia or the ammonium salts used is appropriatelyselected usually from the range of 0.9 to 20 moles, or more preferablyfrom the range of 1 to 15 moles per 1 mole of the optically activeβ-amino acid derivatives (5).

The reaction may be carried out, if necessary, in an atmosphere of inertgases. Examples of the inert gases include nitrogen and argon.

The amidation is preferably carried out in alcoholic solvents and water.Examples of such alcoholic solvents include alcohols such as methanol,ethanol, 2-propanol, 1-butanol, 2-butanol, 2-ethoxyethanol, benzylalcohol, etc.

These solvents may be used solely, or in optional combination of two ormore solvents thereof.

The amount of the solvent used is appropriately selected usually fromthe range of 0.5 to 10 times, or preferably from the range of 0.5 to 5times the volume of the optically active β-amino acid derivatives (5).

The reaction temperature is appropriately selected usually from therange of 0 to 150° C., or preferably from the range of 15 to 120° C.

The reaction time is appropriately selected usually from the range of 10minutes to 96 hours, or more preferably from the range of 30 minute to48 hours.

The optically active amides (6) obtained can be appropriatelyalkoxycarbonylated by the reaction with halogenoformates of, forexample, formula (14) (hereinafter called halogenoformates),R⁸OCOX²  (14)wherein X² is a halogen atom and R⁸ has the same meanings as mentionedabove.

Examples of the halogen atoms represented by X² include a fluorine atom,a chlorine atom, a bromine atom and an iodine atom. Among them, achlorine atom is preferable.

Examples of the halogenoformates include compounds such as methylchloroformate, ethyl chloroformate, propyl chloroformate, butylchloroformate, benzyl chloroformate, etc.

The amount of the halogenoformates used is appropriately selectedusually from the range of 1.0 to 2.0 equivalents, or more preferablyfrom the range of 1.0 to 1.5 equivalents to the optically active amides(6) used.

The reaction may be carried out, if necessary, in an atmosphere of inertgas. Examples of the inert gas include nitrogen and argon.

Examples of the solvent include aliphatic hydrocarbons such as pentane,hexane, heptane, octane, decane, cyclohexane, etc.; aromatichydrocarbons such as benzene, toluene, xylene, etc.; halogenatedhydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform,carbon tetrachloride, o-dichlorobenzene, etc.; ethers such as diethylether, diisopropyl ether, tert-butyl methyl ether, dimethoxyethane,ethyleneglycol diethyl ether, tetrahydrofuran, 1,4-dioxane,1,3-dioxolane, etc.; ketones such as acetone, methyl ethyl ketone,methyl isobutyl ketone, cyclohexanone, etc.; esters such as methylacetate, ethyl acetate, n-butyl acetate, methyl propionate, etc.; amidessuch as N,N-dimethylformamide, N,N-dimethylacetamide, etc; sulfoxidessuch as dimethyl sulfoxide, etc.; cyano-containing organic compoundssuch as acetonitrile, etc; and N-methylpyrrolidone. These solvents maybe used solely or in optional combination of two or more solventsthereof.

The amount of solvent used is appropriately selected usually from therange of 1.0 to 10 times, or preferably from the range of 2.0 to 6.0times the volume of the optically active amides (6).

The alkoxycarbonylation is preferably carried out in the presence ofbases. The bases may be inorganic bases or organic bases, and examplesof the inorganic bases include metal hydroxides such as sodiumhydroxide, potassium hydroxide, lithium hydroxide, etc.; metalcarbonates such as sodium carbonate, potassium carbonate, etc.; metalbicarbonates such as sodium bicarbonate, potassium bicarbonate, etc. andmetal hydrides such as sodium hydride, etc. Examples of the organicbases include alkali metal alkoxides such as potassium methoxide, sodiummethoxide, lithium methoxide, sodium ethoxide, lithium tert-butoxide,potassium tert-butoxide, etc.; and organic amines such as triethylamine,diisopropylethylamine, N,N-dimethylaniline, piperidine, pyridine,4-dimethylaminopyridine, 1,5-diazabicyclo[4.3.0]non-5-ene,1,8-diazabicyclo[5.4.0]undec-7-ene, tri-n-butylamine,N-methylmorpholine, etc.

The amount of the base used is appropriately selected usually from therange of 1.0 to 4.0 equivalents, or more preferably from the range of1.0 to 3.0 equivalents to the optically active amides (6).

The reaction temperature is appropriately selected usually from therange of −20 to 50° C., or more preferably from the range of −5 to 35°C.

The reaction time is appropriately selected usually from the range of 5minutes to 8 hours, or more preferably from the range of 10 minutes to 2hours.

The optically active compounds (7) are subjected to reduction with areducing agent and then directly to cyclization under acidic conditionsto give optically active tetrahydroquinolines (1).

Examples of the reducing agents include such reducing agents as lithiumaluminum hydride, sodium borohydride, borane, etc.; and combinations ofsodium borohydride with Lewis acids. Combinations of sodium borohydridewith Lewis acids are preferable. Examples of the preferable Lewis acidsinclude magnesium compounds and calcium compounds. The reduced compoundsare made to cyclize under acidic conditions giving tetrahydroquinolines.

As to the amount used of the reducing agent, when a combination ofsodium borohydride and a Lewis acid is used as the reducing agent, thesodium borohydride is used usually in 0.5 to 2.0 times, or morepreferably in 0.5 to 1.5 times the moles of the optically activecompounds (7) in mole, and the Lewis acid is used usually in 0.5 to 3.0times, or more preferably in 0.5 to 1.5 times the moles of the compounds(7).

The reaction may be carried out, if necessary, in an atmosphere of inertgas. Examples of the inert gas include nitrogen and argon.

The cyclization is preferably carried out in a solvent. Examples of thesolvent include aliphatic hydrocarbons such as pentane, hexane, heptane,octane, decane, cyclohexane, etc.; aromatic hydrocarbons such asbenzene, toluene, xylene, etc.; halogenated hydrocarbons such asdichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride,o-dichlorobenzene, etc.; ethers such as diethyl ether, diisopropylether, tert-butyl methyl ether, dimethoxyethane, ethyleneglycol diethylether, tetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, etc.; alcohols suchas methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 2-ethoxyethanol,benzyl alcohol, etc.; polyalcohols such as ethylene glycol, propyleneglycol, 1,2-propanediol, glycerol, etc; cyano-containing organiccompounds such as acetonitrile, etc; N-methylpyrrolidone; and water.These solvents may be used solely or in optional combination of two ormore solvents thereof.

The amount of solvent used is appropriately selected usually from therange of 1.0 to 10.0 times, or more preferably from the range of 2.0 to8.0 times the volume of the optically active compound (7).

The cyclization reaction is preferably carried out under acidicconditions with addition of the acids to the reaction system. Variousacids, namely inorganic acids, organic acids, Lewis acids, etc., can beused as the acids. Examples of the inorganic acids include hydrochloricacid, sulfuric acid, phosphoric acid and polyphosphoric acid. Examplesof the organic acids include carboxylic acids such as formic acid,acetic acid, chloroacetic acid, dichloroacetic acid, trichloroaceticacid, trifluoroacetic acid, malic acid, citric acid etc.; sulfonic acidssuch as benzenesulfonic acid, para-toluenesulfonic acid, methanesulfonicacid, camphor-sulfonic acid, etc.; solid acids such as ion-exchangeresins containing functional groups such as sulfo, carboxyl, etc.Examples of the Lewis acids include titanium tetrachloride, borontrifluoride etherate, zinc chloride, scandium triflate, lanthanetriflate, tri(tert-butyl)borate, etc. Among these acids, inorganic acidssuch as hydrochloric acid, sulfuric acid, phosphoric acid, etc. arepreferable.

The amount used of the acid is appropriately selected usually from therange of 0.01 to 50 equivalents, or preferably from the range of 0.5 to30 equivalents to the amount of the optically active compounds (7) used.

The reaction temperature is appropriately selected usually from therange of −30 to 80° C., or preferably from the range of −15 to 40° C.

The reaction may be carried out, if necessary, in an atmosphere of inertgas. Examples of the inert gas include nitrogen and argon.

The optically active tetrahydroquinolines (1) thus obtained are offormulae (18a) to (18d).

Furthermore, the cyclization product, optically activetetrahydroquinolines (1), are those of formula (18a) and/or (18d) below,when optically active compounds of formula (17a) above are used as theoptically active compounds (7), and those of formula (18b) and/or (18c)below, when optically active compounds of formula (17b) above are used:

wherein, R¹ and R⁴ to R⁸ have the same meanings as mentioned above.

Among the thus obtained optically active tetrahydroquinolines offormulae (18a) to (18d) above, the tetrahydroquinolines of formulae(18a) and (18b) above are preferable, the tetrahydroquinolines offormulae (18a) above is more preferable.

The optically active tetrahydroquinolines (1) thus obtained areoptically active 1,2,3,4-tetrahydroquinolines.

The production method of the present invention also makes it possible toproduce optically active compounds (7) with still higher efficiency byreacting optically active β-amino acid derivatives (5) with carbamatesof formula (8) (hereinafter called carbamates (8)).

Examples of the carbamates (8) include methyl carbamate, ethylcarbamate, isopropyl carbamate, butyl carbamate, and benzyl carbamate,etc.

As to the amounts used of the optically active β-amino acid derivatives(5) and the carbamates (8), the amount used of the carbamates (8) isappropriately selected usually from the range of 1.0 to 5.0 equivalents,or preferably from the range of 1.0 to 3.0 equivalents to that ofoptically active β-amino acid derivatives.

The reaction of the optically active β-amino acid derivatives (5) withthe carbamates (8) is preferably carried out in a solvent. Examples ofthe solvent include aliphatic hydrocarbons such as pentane, hexane,heptane, octane, decane, cyclohexane, etc.; aromatic hydrocarbons suchas benzene, toluene, xylene, etc.; halogenated hydrocarbons such asdichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride,o-dichlorobenzene, etc.; ethers such as diethyl ether, diisopropylether, tert-butyl methyl ether, dimethoxyethane, ethyleneglycol diethylether, tetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, etc.; ketones suchas acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone,etc.; alcohols such as methanol, ethanol, 2-propanol, 1-butanol,2-butanol, 2-ethoxyethanol, benzyl alcohol, etc.; polyalcohols such asethylene glycol, propylene glycol, 1,2-propanediol, glycerol, etc.;amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide,etc; sulfoxides such as dimethyl sulfoxide, etc.; cyano-containingorganic compounds such as acetonitrile, etc; and N-methylpyrrolidone.These solvents may be used solely or in optional combination of two ormore solvents thereof.

The amount of solvent used is appropriately selected usually from therange of 1.0 to 10.0 times, or more preferably from the range of 2.0 to8.0 times the volume of the optically active β-amino acid derivatives(5).

The carbamate forming reaction of the optically active β-amino acidderivatives (5) with the carbamates (8) is preferably carried out in thepresence of bases. The bases may be inorganic bases, organic bases, etc.and examples of the inorganic bases include metal hydroxides such assodium hydroxide, potassium hydroxide, lithium hydroxide, etc.; metalcarbonates such as sodium carbonate, potassium carbonate, etc.; metalbicarbonates such as sodium bicarbonate, potassium bicarbonate, etc.;and metal hydrides such as sodium hydride, etc. Examples of the organicbases include alkali metal alkoxides such as potassium methoxide, sodiummethoxide, lithium methoxide, sodium ethoxide, lithium tert-butoxide,potassium tert-butoxide, etc.; organic amines such as triethylamine,diisopropylethylamine, N,N-dimethylaniline, piperidine, pyridine,4-dimethylaminopyridine, 1,5-diazabicyclo[4.3.0]non-5-ene,1,8-diazabicyclo[5.4.0]undec-7-ene, tri-n-butylamine,N-methylmorpholine, etc.

The amount used of the base is appropriately selected usually from therange of 0.5 to 3.0 equivalents, or preferably 0.8 to 2.0 equivalents tothe optically active β-amino acid derivatives (5).

The reaction temperature is appropriately selected usually from therange of −20 to 80° C., or preferably of −5 to 40° C.

The reaction time is appropriately selected usually from the range of 5minutes to 10 hours, or preferably from the range of 10 minutes to 8hours.

The reaction may be carried out, if necessary, in an atmosphere of inertgas. Examples of the inert gas include nitrogen and argon.

In the reaction of the optically active β-amino acid derivatives (5) andthe carbamates (8), the optically active compounds (7) produced are theoptically active compounds of formula (17a) above, when the opticallyactive β-amino acid derivatives of formula (15a) above are used as theoptically active β-amino acid derivatives (5), and the optically activecompounds of formula (17b) above, when the optically active β-amino acidderivatives of formula (15b) above are used.

In the production method of the present invention of optically activeβ-amino acid derivatives of formula (5a) above, said optically activeβ-amino acid derivatives of formula (5a) are obtained readily bysubjecting the enaminoesters of formula (4a) above to asymmetrichydrogenation. Here, when R in formulae (4a) and (5a) is OR², theenaminoesters represented by formula (4a) above are enaminoesters offormula (4) above, and the optically active β-amino acid derivativesrepresented by formula (5a) above obtained are the optically activeβ-amino acid derivatives of formula (5) above.

The optical purity of the optically active tetrahydro-quinolines (1)obtained by the production method of the present invention equal to orhigher than 85% e.e., preferably 90% e.e.

In the production method of the present invention of optically activeβ-amino acid derivatives of formula (22) above, said optically activeβ-amino acid derivatives of formula (22) can be obtained readily bysubjecting the enamino compounds of formula (21) above to asymmetrichydrogenation.

In formulae (21) and (22), the terms: a hydrocarbon group, an aliphaticheterocyclic group, an aromatic heterocyclic group, an aryloxy group, analkoxycarbonyl group, an aryloxycarbonyl group, an acyloxy group, asubstituted hydrocarbon group, a substituted aryl group, a substitutedaralkyl group, a substituted aliphatic heterocyclic group, a substitutedaromatic heterocyclic group, a substituted alkoxy group, a substitutedaryloxy group, a substituted aralkyloxy group, a substituted aminogroup, etc. have the same meanings as mentioned above.

Furthermore, in formula (22),

wherein symbols have each the same meaning as mentioned above, when R²²is a hydrogen, the carbon atom to which R²² binds is not an asymmetriccarbon atom, and when R²³ is a hydrogen atom, the carbon atom to whichR²³ binds is not an asymmetric carbon atom.

The asymmetric hydrogenation of the present invention of enaminocompounds of formula (21)

gives the optically active β-amino acid derivatives represented byformula (22) above efficiently and in excellent asymmetric yields.

Specific examples of the enamino compounds of formula (21) include, inaddition to the compounds specifically exemplified above asenaminoesters (4), compounds as follows.

Specific examples of the optically active β-amino acid derivatives offormula (22) include, in addition to the compounds specificallyexemplified above as optically active β-amino acid derivatives (5),compounds as follows.

The asymmetric hydrogenation catalysts, solvents, reaction conditions,and so on which are used in the asymmetric hydrogenation, are the sameas those described above in the asymmetric hydrogenation of theenaminoesters (4).

EXAMPLES

The present invention will be described in more detail referring toExamples, although the present invention is not restricted to theseExamples.

The apparatus used for measuring physical characteristics, etc. inExamples below is as follows:

(1) Nuclear Magnetic Resonance Spectrum: DRX 500 (BRUKER JAPAN Co.Ltd.), ¹H-NMR (500.13 MHz), ¹³C-NMR (125.76 MHz)

(2) Gas chromatography (GLC): Hewlett Packard 5890-II

(3) High Performance Liquid Chromatography (HPLC): Shimadzu LC10AT &-SPD10A

Example 1 Preparation of methyl3-(4-trifluoromethylphenylamino)-2-pentenoate

In a 500-ml flask, 4-trifluoromethylaniline (80.6 g, 0.5 mol), methyl3-oxopentanoate (65.1 g, 0.5 mol) and toluene 400 ml were placed. Tothis solution was added boron trifluoride etherate (1.42 g, 10 mmol),and the resulting mixture was heated under a reduced pressure of 8 kPa.The reaction mixture was heated for 5 hours under reflux, while waterproduced was removed out of the reaction system by using a Dean-Starktrap. Then, the heating was discontinued and nitrogen was leaked. Aftercooling, the solvent was removed by distillation by using a rotaryevaporator. The residue was then distilled under reduced pressure togive 105.3 g of the title compound. The yield was 77.1%.

¹H-NMR (CDCl₃, δppm): 10.52 (bs, 1H), 7.57 (d, J=8.5 Hz, 2H), 7.16(d,J=8.5 Hz, 2H), 4.85 (s, 1H), 3.70 (s, 3H), 2.42 (d, J=7.4 Hz, 2H), 1.08(t, J=7.4 Hz, 3H).

Example 2 Preparation of methyl3(R)-3-(4-trifluoromethylphenylamino)pentanoate

Methyl 3-(4-trifluoromethylphenylamino)-2-pentenoate (100 g, 0.366 mol),2-propanol (200 ml) and [{RuCl((R)-segphos)}₂(μ-Cl)₃][Me₂NH₂] (301 mg,0.183 mmol) were placed in a 1 L-autoclave under atmosphere of nitrogen,and hydrogenation was carried out at 95° C., under a hydrogen pressureof 5 MPa for 2 hours (conversion: 100%). The solvent was removed byevaporation under reduced pressure, and the residue was distilled underreduced pressure (bp 120° C./400 Pa) to give 85.6 g of the titlecompound (a liquid). The yield was 85.0%.

Chemical purity: 100%

Optical purity: 96.0% e.e.

¹H-NMR (CDCl₃, δppm): 7.39 (d, J=8.3 Hz, 2H), 6.62 (d, J=8.5 Hz, 2H),4.13 (bs, 1H), 3.81-3.77 (m, 1H), 3.66 (s, 3H), 2.55 (d, J=6.1 Hz, 2H),1.68-1.58 (m, 2H), 0.97 (t, J=7.4 Hz, 3H).

Example 3 Preparation of methyl3(S)-3-(4-trifluoromethylphenylamino)-2-pentanoate

Methyl 3-(4-trifluoromethylphenylamino)-2-pentenoate (190 g, 0.695 mol),2-propanol (380 ml), [{RuCl((S)-segphos)}₂(μ-Cl)₃][Me₂NH₂] (572.5 mg,0.348 mmol) were placed in a 1 L-autoclave in a stream of nitrogen, andhydrogenation was carried out at 95° C. under a hydrogen pressure of 5MPa for 1.5 hours (conversion: 100%). The solvent was removed byevaporation under reduced pressure, and the residue was distilled underreduced pressure (bp 120° C./400 Pa) to give 160.0 g of the titlecompound (a liquid). The yield was 84.0%.

Chemical purity: 100%

Optical purity: 93.1% e.e.

¹H-NMR (CDCl₃, δppm): 7.39 (d, J=8.3 Hz, 2H), 6.62 (d, J=8.5 Hz, 2H),4.13 (bs, 1H), 3.81-3.77 (m, 1H), 3.66 (s, 3H), 2.55 (d, J=6.1 Hz, 2H),1.68-1.58 (m, 2H), 0.97 (t, J=7.4 Hz, 3H).

Example 4 Preparation of3(R)-3-(4-trifluoromethylphenylamino)pentanamide

Methyl 3(R)-3-(4-trifluoromethylphenylamino)pentanoate (5.5 g, 20.0mmol) and 12.8% ammonia-methanol solution (26.6 g, 200 mmol) were placedin a 100-ml autoclave. The mixture was made to react at 100° C. for 48hours. After cooling to room temperature, the solvent was removed byevaporation and the residue purified by chromatography on silica gel togive 3.0 g of the title compound as crystals. The yield was 57.7%.

Optical purity: 96% e.e.

¹H-NMR (CDCl₃, δppm): 7.39 (d, J=8.7 Hz, 2H), 6.65 (d, J=8.6 Hz, 2H),5.59 (bs, 1H), 5.46 (bs, 1H), 4.29 (bd, J=6.4 Hz, 1H), 3.81-3.74 (m,1H), 2.47 (dd, J=5.5 Hz, 15.1 Hz, 1H), 2.43 (dd, J=5.8 Hz, 15.0 Hz, 1H),1.75-1.62 (m, 2H), 0.99 (t, J=7.4 Hz, 3H).

Example 5 Preparation of methyl3(R)-3-(4-trifluoromethylphenylamino)pentanoylcarbamate

In an atmosphere of nitrogen,3(R)-3-(4-trifluoromethylphenylamino)-2-pentanamide (3.0 g, 11.5 mmol)and methyl chlorocarbonate (1.35 g, 14.3 mmol) were mixed in 15 ml ofdiisopropyl ether, and the mixture was stirred under cooling with ice.To this solution, a THF-hexane solution of lithium tert-butoxideprepared from 1.6-M n-butyllithium (15.2 ml, 24.3 mmol) and tert-butanol(1.8 g, 24.3 mmol) was added dropwise at the temperature of not morethan 5° C. After completion of the addition, the mixture was stirred atthe same temperature for 30 minutes. Then, the reaction was quenchedwith 1M hydrochloric acid. The organic layer was separated, washedsuccessively with a saturated solution of sodium chloride and water. Thesolvent was then removed by evaporation to give 3.41 g of the titlecompound. The yield was 93%.

Optical purity: 96% e.e.

¹H-NMR (acetone-d₆, δppm): 9.36 (bs, 1H), 7.37 (d, J=8.6 Hz, 2H), 6.77(d, J=8.6 Hz, 2H), 5.46 (bd, J=8.9 Hz, 1H), 4.00-3.93 (m, 1H), 3.69 (s,3H), 2.96 (dd, J=6.2 Hz, 16.2 Hz, 1H), 2.86 (dd, J=6.3 Hz, 16.1 Hz, 1H),1.77-1.68 (m, 1H), 1.66-1.57 (m, 1H), 0.97 (t, J=7.5 Hz, 3H).

Example 6 Preparation of methyl3(R)-3-(4-trifluoromethylphenylamino)pentanoylcarbamate

In a Schlenk-tube of which atmosphere had been replaced with nitrogen,60% sodium hydride (60 mg, 1.5 mmol) was suspended in tetrahydrofuran(THF) (1 ml). To this suspension was added dropwise a THF (1 ml)solution of methyl carbamate (255 mg, 3.4 mmol) at room temperature.After stirring for 10 minutes, a solution of methyl3(R)-3-(4-trfluoromethylphenylamino)pentanoate (500 mg, 1.8 mmol) in THF(1 ml) was added dropwise and the resulting solution was stirred for 1hour. The reaction mixture was poured into a mixture of ethyl acetateand a saturated aqueous solution of sodium bicarbonate. The organiclayer was separated and the water layer was further extracted twice withethyl acetate. The organic layers were combined, dried over magnesiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by chromatography on silica gel to give 334 mg of the titlecompound as white crystals. The yield was 58%. Optical purity: 96% e.e.

The ¹H-NMR spectrum of the product was identical to that of Example 5.

Example 7 Preparation of methyl(2R,4S)-(2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate

In an atmosphere of nitrogen, methyl3(R)-3-(4-trifluoromethylphenylamino)pentanoyl carbamate (1.0 g, 3.1mmol) and 95% ethanol (6.3 ml) were mixed and the mixture was stirred atroom temperature. To this solution was added sodium borohydride (83 mg,2.2 mmol), and the resulting mixture was stirred at room temperature for30 minutes and then cooled to −10° C. To the resulting suspension wasadded an aqueous solution of magnesium chloride (579 mg, 285 mmol) at atemperature not more than −5° C. The mixture was stirred at 0° C. for 1hour, and then added dropwise to a mixture of a solution of citric acidmonohydrate (1.45 g, 6.9 mmol) in 1M hydrochloric acid and methylenechloride (20 ml). The resulting mixture was stirred at room temperaturefor 2 hours. The organic layer was separated and treated with an aqueoussolution of citric acid monohydrate (660 mg, 3.1 mmol) in water (6 ml)with stirring at room temperature for 1 hour. The organic layer wasseparated, washed with water, and the solvent was removed by evaporationto give 845 mg of the title compound. The yield was 89%.

Optical purity: 96% e.e.

¹H-NMR (acetone-d₆, δppm): 7.31 (bs, 1H), 7.19 (d, J=8.5 Hz, 1H), 6.65(d, J=8.4 Hz, 1H), 6.51 (bd, J=9.0 Hz, 1H), 5.61 (bs, 1H), 4.95-4.90 (m,1H), 3.67 (s, 3H), 3.51-3.46 (m, 1H), 2.21-2.17 (m, 1H), 1.65-1.54 (m,3H), 1.00 (t, J=7.5 Hz, 3H).

Example 8 Preparation of methyl3(R)-3-(4-trifluoromethylphenylamino)pentanoate

Methyl 3-(4-trifluoromethylphenylamino)-2-pentenoate (100 g, 0.366 mol),2-propanol (150 ml) and [{RuCl((R)-segphos)}₂(μ-Cl)₃][Me₂NH₂] (301 mg,0.183 mmol) were placed in a 1 L-autoclave in a stream of nitrogen, andhydrogenation was carried out at 95° C. under a hydrogen pressure of 5MPa for 6 hours (conversion: 100%). The solvent was removed byevaporation under reduced pressure, and the residue was distilled underreduced pressure (bp 120° C./400 Pa) to give 91.4 g of the titlecompound (a liquid). The yield was 90.7%.

Chemical purity: 100%

Optical yield: 94.0% e.e.

The ¹H-NMR spectrum was identical to that of Example 2.

Example 9 Preparation of 3(R)-3-(4-trifluoromethylphenylamino)pentanoate

Methyl 3-(4-trifluoromethylphenylamino)-2-pentenoate (100 g, 0.366 mol),2-propanol (150 ml) and [{RuCl((R)-t-binap)}₂(μ-Cl)₃][Me₂NH₂] (326 mg,0.183 mmol) were placed in a 1 L-autoclave in a stream of nitrogen, andhydrogenation was carried out at 95° C. under a hydrogen pressure of 3MPa for 6 hours (conversion: 100%). The solvent was removed byevaporation under reduced pressure, and the residue was distilled underreduced pressure (bp 120° C./400 Pa) to give 81.8 g of the titlecompound (a liquid). The yield was 81.2%.

Chemical purity: 100%

Optical purity: 94.2% e.e.

The ¹H-NMR spectrum was identical to that of Example 2.

Example 10 Preparation of methyl3(S)-3-(4-trifluoromethylphenylamino)pentanoate

Methyl 3-(4-trifluoromethylphenylamino)-2-pentenoate (190 g, 0.695 mol),2-butanol (380 ml) and [Ru(p-cymene)Cl((S)-segphos)]Cl (637 mg, 0.695mmol) were placed in a 1 L-autoclave in a stream of nitrogen, andhydrogenation was carried out at 75° C., under a hydrogen pressure of 5MPa for 14 hours (conversion: 100%). The solvent was removed byevaporation under reduced pressure, and the residue was distilled underreduced pressure (bp 120° C./400 Pa) to give 130.3 g of the titlecompound (a liquid). The yield was 68.1%.

Chemical purity: 100%.

Optical purity: 96.7% e.e.

The ¹H-NMR spectrum was identical to that of Example 3.

Example 11 Preparation of methyl3-(4-trifluoromethylphenylamino)-2-pentenoate

In a 1 L-flask were placed 4-trifluoromethylaniline (161 g, 1.00 mol),methyl 3-oxopentanoate (130 g, 1.00 mol) and toluene (160 mL). To thissolution was added acetic acid (16 g, 0.27 mol), and the resultingmixture was heated in a bath kept at 100° C. under a reduced pressure of19 kPa for 3.5 hours, while the water generated was taken out of thereaction system by using a Dean-Stark trap under reflux. Acetic acid (16g, 0.27 mol) was then added, and reflux was continued for 4.5 hours.Acetic acid (8 g, 0.13 mol) was then added again, and reflux wascontinued for another 2.5 hours. The heating was then discontinued,nitrogen leaked in, and the reaction mixture cooled. After distillationof the solvent and acetic acid under reduced pressure, the residue wasdistilled under reduced pressure to give 199 g of the title compound.The yield was 72.8%.

The ¹H-NMR spectrum was identical to that of Example 1.

Example 12 Preparation of methyl3-(4-trifluoromethylphenylamino)-2-pentenoate

In a 2L-flask were placed 4-trifluoromethylaniline (161 g, 1.00 mol),methyl 3-oxopentanoate (143 g, 1.10 mol) and toluene (640 ml). To thissolution was added p-toluenesulfonic acid monohydrate (3.2 g, 0.017mol), and the resulting mixture was heated in a bath kept at 100° C.under a reduced pressure of 27 kPa, while the water generated was takenout of the reaction system by using a Dean-Stark trap under reflux.After 15 hours, the heating was discontinued, nitrogen leaked in, andthe reaction mixture cooled. The solvent was evaporated by means of arotary-evaporator, and the residue was distilled under reduced pressureto give 207 g of the title compound. The yield was 75.8%.

The ¹H-NMR spectrum was identical to that of Example 1.

Example 13 Preparation of methyl3-(4-trifluoromethylphenylamino)-2-pentenoate

In a 500 ml-flask were placed 4-trifluoromethylanline (48.3 g, 0.30mol), methyl 3-oxopentanoate (43.0 g, 0.33 mol) and toluene (192 ml). Tothis solution was added 4.8 g of solid acid catalyst (Amberlyst No. 31WET type, product of Rohm and Haas Co.), and the resulting mixture washeated in a bath kept at 100° C. under a reduced pressure of 25 kPa for11 hours, while removing the water formed under reflux by using aDean-Stark trap. The heating was then discontinued, nitrogen leaked in,and the reaction mixture cooled. The catalyst was filtered off and thesolvent evaporated off by using a rotary evaporator, and the residue wasdistilled under reduced pressure to give 213 g of the title compound.The yield was 77.8%.

The ¹H-NMR spectrum was identical to that of Example 1.

Example 14 Preparation of methyl3-(4-trifluoromethylphenylamino)-2-pentenoate

4-Trifluoromethylanline (161 g, 1.00 mol), methyl 3-oxopentanoate (143g, 1.10 mol) and toluene (640 ml) were placed in a 2L-flask. To thissolution was added tri(tert-butyl)borate (22.7 g, 0.10 mol), and theresulting mixture was heated in a bath kept at 100° C. under a reducedpressure of 27 kPa for 6 hours, while removing the water formed byrefluxing by using a Dean-Stark trap. The heating was then discontinued,nitrogen leaked in, and the reaction mixture cooled. The solvent wasevaporated off by using a rotary-evaporator, and the residue wasdistilled under reduced pressure to give 212 g of the title compound.The yield was 77.6%.

The ¹H-NMR spectrum was identical to that of Example 1.

Example 15 Preparation of methyl3-(2-trifluoromethylphenylamino)-2-pentenoate

In a 100 ml-flask were placed 2-trifluoromethylanline (25.0 g, 155mmol), methyl 3-oxopentanoate (22.2 g, 171 mmol) and toluene (100 ml).To this solution was added p-toluenesulfonic acid monohydrate (0.15 g,0.79 mmol), and the resulting mixture was heated in a bath kept at 100°C. under a reduced pressure of 27 kPa for 5 hours, while removing thewater formed by refluxing by using a Dean-Stark trap. The heating wasthen discontinued, nitrogen leaked in, and the reaction mixture cooled.After evaporation of the solvent by using a rotary evaporator, theresidue was distilled under reduced pressure to give 14.0 g of the titlecompound. The yield was 32.7%.

¹H-NMR (CDCl₃, δppm): 10.28 (bs, 1H), 7.68 (d, J=7.3 Hz, 1H), 7.52 (t,J=7.5 Hz, 1H), 7.30 (t, J=7.7 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 4.86 (s,1H), 3.71 (s, 3H), 2.25 (q, J=7.5 Hz, 2H) and 1.00 (t, J=2.5 Hz, 3H).

Example 16 Preparation of methyl3-(3-trifluoromethylphenylamino)-2-pentenoate

In a 100 ml-flask were placed 3-trifluoromethylanline (20.0 g, 124mmol), methyl 3-oxopentanoate (17.8 g, 136 mmol) and toluene (80 ml). Tothis solution was added p-toluenesulfonic acid monohydrate (0.12 g, 0.62mmol), and the resulting mixture was heated in a bath kept at 100° C.under a reduced pressure of 29 kPa for 2.5 hours, while removing thewater formed by refluxing by using a Dean-Stark trap. The heating wasthen discontinued, nitrogen leaked in, and the reaction mixture cooled.The solvent was evaporated off by using a rotary evaporator, and theresidue was distilled under reduced pressure to give 24.4 g of the titlecompound. The yield was 71.9%.

¹H-NMR (CDCl₃, δppm): 10.42 (bs, 1H), 7.46-7.39 (m, 2H), 7.34 (s, 1H),7.27 (d, J=6.5 Hz, 1H), 4.82 (s, 1H), 3.70 (s, 3H), 2.36 (q, J=7.5 Hz,2H), 1.07 (t, J=7.5 Hz, 3H).

Example 17 Preparation of methyl 3-(4-chlorophenylamino)-2-pentenoate

In a 300 ml-flask were placed 4-chloroaniline (25.0 g, 196 mmol), methyl3-oxopentanoate (28.1 g, 216 mmol) and toluene (100 ml). To thissolution was added p-toluenesulfonic acid monohydrate (0.19 g, 0.98mmol), and the resulting mixture was heated in a bath kept at 100° C.under a reduced pressure of 23 kPa for 2.5 hours, while removing thewater formed by refluxing by using a Dean-Stark trap. The heating wasthen discontinued, nitrogen leaked in, and the reaction mixture cooled.The solvent was evaporated off by using a rotary evaporator, and theresidue was distilled under reduced pressure to give 33.1 g of the titlecompound. The yield was 70.5%.

¹H-NMR (CDCl₃, δppm): 10.25 (bs, 1H), 7.29 (d, J=6.6 Hz, 2H), 7.03 (d,J=6.7 Hz, 2H), 4.76 (s, 1H), 3.69 (s, 3H), 2.30 (q, J=7.5 Hz, 2H), 1.04(t, J=7.5 Hz, 3H).

Example 18 Preparation of methyl3-(4-trifluoromethylphenylamino)-2-butenoate

In a 1 L-flask were placed 4-trifluoromethylanline (120 g, 0.745 mol),methyl acetoacetate (130 g, 1.12 mol) and toluene (360 ml). To thissolution was added p-toluenesulfonic acid monohydrate (0.6 g, 0.003mol), and the resulting mixture was heated in a bath kept at 100° C.under a reduced pressure of 27 kPa for 3 hours, while removing the waterformed by refluxing by using a Dean-Stark trap. The heating was thendiscontinued, nitrogen leaked in, and the reaction mixture cooled. Thesolvent was evaporated off by using a rotary-evaporator, and the residuewas distilled under reduced pressure to give 126 g of the titlecompound. The yield was 65.3%.

¹H-NMR (CDCl₃, δppm): 7.42 (d, J=7.8 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H),6.79 (d, J=8.3 Hz, 1H), 6.70 (t, J=7.6 Hz, 1H), 4.41 (bs, 1H), 3.89-3.81(m, 1H), 3.68 (s, 3H), 2.62 (dd, J=5.6 Hz, 15.2 Hz, 1H), 2.52 (dd, J=6.6Hz, 15.2 Hz, 1H), 1.73-1.50 (m, 2H), 0.98 (t, J=7.4 Hz, 3H).

Example 19 Preparation of methyl3(R)-3-(2-trifluoromethylphenylamino)pentanoate

Methyl 3-(2-trifluoromethylphenylamino)-2-pentenoate (10.0 g, 36.6mmol), 2-butanol (20 ml) and [RuCl(p-cymene)((R)-segphos)]Cl (33.6 mg,0.037 mmol) were placed in a 200 ml-autoclave in a stream of nitrogen,and asymmetric hydrogenation was carried out at 70° C., under a hydrogenpressure of 3 MPa for 6 hours (conversion: 100%). The solvent wasevaporated off under reduced pressure, and the residue was distilledunder reduced pressure to give 9.1 g of the title compound (a liquid).The yield was 91%.

Chemical purity: 100%,

¹H-NMR (CDCl₃, δppm): 7.42 (d, J=7.8 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H),6.79 (d, J=8.3 Hz, 1H), 6.70 (t, J=7.6 Hz, 1H), 4.41 (bd, J=7.8 Hz, 1H),3.89-3.81 (m, 1H), 3.68 (s, 3H), 2.57 (ddd, J=5.6 Hz, 15.2 Hz, 29.6 Hz,2H), 1.73-1.50 (m, 2H), 0.98 (t, J=7.4 Hz, 3H).

Example 20 Preparation of methyl3(R)-3-(3-trifluoromethylphenylamino)pentanoate

Methyl 3-(3-trifluoromethylphenylamino)-2-pentenoate (2.0 g, 7.3 mmol),2-butanol (4.0 ml), [RuCl(p-cymene)((R)-segphos)]Cl (13.4 mg, 0.015mmol) were placed in a 100 ml-autoclave in a stream of nitrogen, andasymmetric hydrogenation was carried out at 70° C., under a hydrogenpressure of 5 MPa for 16 hours (conversion: 100%). The solvent wasremoved by evaporation under reduced pressure, and the residue wasdistilled under reduced pressure to give 1.2 g of the title compound (aliquid). The yield was 60%.

Chemical purity: 100%

Optical purity: 91.5% e.e.

¹H-NMR (CDCl₃, δppm): 7.24 (t, J=8.4 Hz, 1H), 6.91 (d, J=7.7 Hz, 1H),6.81 (s, 1H), 6.76 (d, J=8.2 Hz, 1H), 3.98 (bs, 1H), 3.81-3.73 (m, 1H),3.66 (s, 3H), 2.54 (d, J=5.9 Hz, 2H), 1.70-1.57 (m, 2H), 0.98 (t, J=7.4Hz, 3H).

Example 21 Preparation of methyl 3(R)-3-(4-chlorophenylamino)pentanoate

Methyl 3-(4-chlorophenylamino)-2-pentenoate (2.0 g, 8.3 mmol), 2-butanol(4 ml) and [RuCl(p-cymene)((R)-segphos)]Cl (7.7 mg, 0.008 mmol) wereplaced in a 100 ml-autoclave in a stream of nitrogen, and asymmetrichydrogenation was carried out at 70° C. under a hydrogen pressure of 3MPa for 17 hours (conversion: 100%). The solvent was removed byevaporation under reduced pressure, and the residue was distilled underreduced pressure to give 1.75 g of the title compound (a liquid). Theyield was 87%.

Chemical purity: 100%

Optical purity: 87.8% e.e.

¹H-NMR (CDCl₃, δppm): 7.10 (d, J=6.4 Hz, 2H), 6.54 (d, J=6.7 Hz, 2H),3.72 (bs, 1H), 3.73-3.66 (m, 1H), 3.66 (s, 3H), 2.56-2.47 (m, 2H),1.64-1.55 (m, 2H), 0.96 (t, J=7.5 Hz, 3H).

Example 22 Preparation of methyl3(R)-3-(4-trifluoromethylphenylamino)butanoate

Methyl 3-(4-trifluoromethylphenylamino)-2-butenoate (111 g, 428 mmol),2-butanol (220 ml) and [RuCl(p-cymene)((R)-segphos)]Cl (393 mg, 0.428mmol) were placed in a 1 L-autoclave in a stream of nitrogen, andasymmetric hydrogenation was carried out at 70° C. under a hydrogenpressure of 3 MPa for 17 hours (conversion: 100%). The solvent wasremoved by evaporation under reduced pressure, and the residue wasdistilled under reduced pressure to give 95.8 g of the title compound (aliquid). The yield was 86.4%.

Chemical purity: 100%

Optical purity: 87.4% e.e.

¹H-NMR (CDCl₃, δppm): 7.40 (d, J=8.8 Hz, 2H), 6.62 (d, J=8.6 Hz, 2H),4.17 (bs, 1H), 4.01-3.95 (m, 1H), 3.69 (s, 3H), 2.62 (dd, J=5.3 Hz, 6.1Hz, 1H), 2.48 (dd, J=6.6 Hz, 15.2 Hz, 1H), 1.30 (t, J=6.4 Hz, 3H).

Example 23 Preparation of methyl3-(3,5-dichlorophenylamino)-2-pentenoate

In a 300 mL-flask were placed 3,5-dichloroaniline (25.0 g, 154 mmol),methyl 3-oxopentanoate (22.1 g, 170 mmol) and toluene (160 mL). To thissolution was added p-toluenesulphonic acid monohydrate (0.59 g, 3.1mmol), and the resulting mixture was heated in a bath kept at 100° C.under a reduced pressure of 21 kPa for 3 hours, while the watergenerated was taken out of the reaction system by using a Dean-Starktrap under reflux. p-Toluenesulphonic acid monohydrate (0.59 g, 3.1mmol) was then added, and reflux was continued for 1 hour. The heatingwas then discontinued, nitrogen leaked in, and the reaction mixturecooled. After distillation of the solvent under reduced pressure, theresidue was distilled under reduced pressure to give 27.4 g of the titlecompound. The yield was 64.8%.

¹H-NMR (500 MHz, CDCl₃, δppm): 10.35 (bs, 1H), 7.13 (t, J=1.8 Hz, 1H),6.98 (d, J=1.8 Hz, 2H), 4.83 (s, 1H), 3.69 (s, 3H), 2.37 (q, J=7.4 Hz,2H), 1.08 (t, J=7.4 Hz, 3H).

Example 24 Preparation of methyl3(R)-3-(3,5-dichlorophenylamino)pentanoate

Methyl 3-(3,5-dichlorophenylamino)pentenoate (2.0 g, 7.3 mmol),2-butanol (4 ml) and [RuCl(p-cymene)((R)-segphos)]Cl (6.7 mg, 0.007mmol) were placed in a 100 ml-autoclave in a stream of nitrogen, andasymmetric hydrogenation was carried out at 80° C. under a hydrogenpressure of 3 MPa for 16 hours (conversion: 100%). The solvent wasremoved by evaporation under reduced pressure, and the residue wasdistilled under reduced pressure to give 1.72 g of the title compound (aliquid). The yield was 85%.

Chemical purity: 100%

Optical purity: 88.4% e.e.

¹H-NMR (500 MHz, CDCl₃, δppm): 6.65 (t, J=1.8 Hz, 1H), 6.47 (d, J=1.8Hz, 2H), 3.98 (bs, 1H), 3.69-3.64 (m, 1H), 3.67 (s, 3H), 2.53 (dd, J=1.3Hz, 5.9 Hz, 2H), 1.66-1.54 (m, 2H), 0.96 (t, J=7.4 Hz, 3H).

INDUSTRIAL APPLICABILITY

One of the features of the production method of the present invention isto carry out the asymmetric hydrogenation of enaminoesters withoutprotecting the secondary amino group with a protective group. Thisbrings about the effect of making it possible to produce the desiredoptically active tetrahydroquinolines via short steps without steps ofintroduction and removal of the protective group, and optically activetetrahydroquinolines with high optical purity.

Another feature of the production method of the present invention is tocarry out the reactions without protecting the secondary amino group ofenaminoesters with a protective group. This brings about the effect ofmaking it possible to produce the desired optically active β-amino acidderivatives via short steps without steps of introduction and removal ofthe protective group.

1. A method for producing an optically active tetrahydroquinoline offormula (1),

wherein R¹ is a hydrocarbon group, a substituted hydrocarbon group orCOOR⁹ (R⁹ is a hydrocarbon group or a substituted hydrocarbon group); R⁴to R⁷ are each independently, a hydrogen atom, a hydrocarbon group, ahalogen atom, a halogenated hydrocarbon group, a substituted hydrocarbongroup, an aliphatic heterocyclic group, a substituted aliphaticheterocyclic group, an aromatic heterocyclic group, a substitutedaromatic heterocyclic group, an alkoxy group, a substituted alkoxygroup, an aralkyloxy group, a substituted aralkyloxy group, an aryloxygroup, a substituted aryloxy group, an acyl group, an acyloxy group, analkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonylgroup, an alkylenedioxy group, a hydroxy group, a nitro group, an aminogroup or a substituted amino group; R⁸ is a hydrocarbon group or asubstituted hydrocarbon group; * shows an asymmetric carbon atom: and R⁴and R⁵, R⁵ and R⁶, or R⁶ and R⁷, taken together, may form a fused ring,which method comprises the following steps: 1) a step of reacting aβ-ketoester of formula (2),

wherein R¹ is a hydrocarbon group, a substituted hydrocarbon group orCOOR⁹ (wherein R⁹ is a hydrocarbon group or a substituted hydrocarbongroup) and R² is a hydrocarbon group or a substituted hydrocarbon group,to react with an amine of formula (3),

wherein R³ to R⁷ are each independently a hydrogen atom, a hydrocarbongroup, a halogen atom, a halogenated hydrocarbon group, a substitutedhydrocarbon group, an aliphatic heterocyclic group, a substitutedaliphatic heterocyclic group, an aromatic heterocyclic group, asubstituted aromatic heterocyclic group, an alkoxy group, a substitutedalkoxy group, an aralkyloxy group, a substituted aralkyloxy group, anaryloxy group, a substituted aryloxy group, an acyl group, an acyloxygroup, an alkoxycarbonyl group, an aryloxycarbonyl group, anaralkyloxycarbonyl group, an alkylenedioxy group, a hydroxy group, anitro group, an amino group or a substituted amino group; and R³ and R⁴,R⁴ and R⁵, R⁵ and R⁶, or R⁶ and R⁷, taken together, may form a fusedring, with the proviso that either R³ or R⁷ is a hydrogen atom, toproduce an enaminoester of formula (4),

wherein R¹ to R⁷ are each the same meaning as mentioned above; 2) a stepof subjecting the enaminoester of formula (4) above obtained in 1) to anasymmetric hydrogenation to produce an optically active β-amino acidderivative of formula (5),

wherein * shows an asymmetric carbon atom and R¹ to R⁷ are each the samemeaning as mentioned above; 3) a step of amidating the optically activeβ-amino acid derivative of formula (5) above obtained in 2) above toproduce an amide of formula (6),

wherein, R¹, R³ to R⁷ and * have the same meanings as those mentionedabove; 4) a step of alkoxycarbonylating the amide of formula (6) aboveobtained in 3) above to produce a compound of formula (7),

wherein R⁸ is a hydrocarbon group or a substituted hydrocarbon group,and R¹, R³ to R⁷ and * have the same meanings as mentoned above; and 5)a step of subjecting the compound of formula (7) above obtained in 4)above to a cyclization to produce an optically activetetrahydroquinoline of formula (1) above.
 2. A method for producing anoptically active tetrahydroquinoline of formula (1),

wherein R¹ is a hydrocarbon group, a substituted hydrocarbon group orCOOR⁹ (R⁹ is a hydrocarbon group or a substituted hydrocarbon group); R⁴to R⁷ are each independently a hydrogen atom, a hydrocarbon group, ahalogen atom, a halogenated hydrocarbon group, a substituted hydrocarbongroup, an aliphatic heterocyclic group, a substituted aliphaticheterocyclic group, an aromatic heterocyclic group, a substitutedaromatic heterocyclic group, an alkoxy group, a substituted alkoxygroup, an aralkyloxy group, a substituted aralkyloxy group, an aryloxygroup, a substituted aryloxy group, an acyl group, an acyloxy group, analkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonylgroup, an alkylenedioxy group, a hydroxy group, a nitro group, an aminogroup or a substituted amino group; R⁸ is a hydrocarbon group or asubstituted hydrocarbon group; * shows an asymmetric carbon atom: and R⁴and R⁵, R⁵ and R⁶, or R⁶ and R⁷, taken together, may form a fused ring,which method comprises the following steps: 1) a step of reacting aβ-ketoester of formula (2),

wherein R¹ is a hydrocarbon group, a substituted hydrocarbon group orCOOR⁹ (R⁹ is a hydrocarbon group or a substituted hydrocarbon group) andR² is a hydrocarbon group or a substituted hydrocarbon group, with anamine of formula (3),

wherein R³ to R⁷ are each independently a hydrogen atom, a hydrocarbongroup, a halogen atom, a halogenated hydrocarbon group, a substitutedhydrocarbon group, an aliphatic heterocyclic group, a substitutedaliphatic heterocyclic group, an aromatic heterocyclic group, asubstituted aromatic heterocyclic group, an alkoxy group, a substitutedalkoxy group, an aralkyloxy group, a substituted aralkyloxy group, anaryloxy group, a substituted aryloxy group, an acyl group, an acyloxygroup, an alkoxycarbonyl group, an aryloxycarbonyl group, anaralkyloxycarbonyl group, an alkylenedioxy group, a hydroxy group, anitro group, an amino group or a substituted amino group; R³ and R⁴, R⁴and R⁵, R⁵ and R⁶, or R⁶ and R⁷, taken together, may form a fused ring,with the proviso that either R³ or R⁷ is a hydrogen atom, to produce anenaminoester of formula (4),

wherein R¹ to R⁷ have the same meanings as mentioned above; 2) a step ofsubjecting the enaminoester of formula (4) above obtained in 1) above toasymmetric hydrogenation to produce an optically active β-amino acidderivative of formula (5),

wherein * shows an asymmetric carbon atom and R¹ to R⁷ have the samemeanings as mentioned above; 3) a step of reacting the optically activeβ-amino acid derivative of formula (5) above obtained in 2) above with acarbamate of formula (8)H₂N—COOR⁸  (8) wherein R⁸ is a hydrocarbon group or a substitutedhydrocarbon group, to produce a compound of formula (7),

wherein R⁸ is a hydrocarbon group or a substituted hydrocarbon group,and R¹, R³ to R⁷ and * have the same meanings as mentioned above, and 4)a step of subjecting the optically active compound of formula (7) aboveobtained in 3) above to a cyclization to produce an optically activetetrahydroquinoline of formula (1) above.
 3. A method for producing anoptically active tetrahydroquinoline of formula (1),

wherein R¹ is a hydrocarbon group, a substituted hydrocarbon group orCOOR⁹ (R⁹ is a hydrocarbon group or a substituted hydrocarbon group); R⁴to R⁷ are each independently a hydrogen atom, a hydrocarbon group, ahalogen atom, a halogenated hydrocarbon group, a substituted hydrocarbongroup, an aliphatic heterocyclic group, a substituted aliphaticheterocyclic group, an aromatic heterocyclic group, a substitutedaromatic heterocyclic group, an alkoxy group, a substituted alkoxygroup, an aralkyloxy group, a substituted aralkyloxy group, an aryloxygroup, a substituted aryloxy group, an acyl group, an acyloxy group, analkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonylgroup, an alkylenedioxy group, a hydroxy group, a nitro group, an aminogroup or a substituted amino group; R⁸ is a hydrocarbon group or asubstituted hydrocarbon group, * shows an asymmetric carbon atom; and R⁴and R⁵, R⁵ and R⁶, or R⁶ and R⁷, taken together, may form a fused ring,which method comprises the following steps: 1) a step of subjecting theenaminoester of formula (4),

wherein R¹ is a hydrocarbon group, a substituted hydrocarbon group orCOOR⁹ (R⁹ is a hydrocarbon group or a substituted hydrocarbon group); R²is a hydrocarbon group or a substituted hydrocarbon group; R³ to R⁷ areeach independently a hydrogen atom, a hydrocarbon group, a halogen atom,a halogenated hydrocarbon group, a substituted hydrocarbon group, analiphatic heterocyclic group, a substituted aliphatic heterocyclicgroup, an aromatic heterocyclic group, a substituted aromaticheterocyclic group, an alkoxy group, a substituted alkoxy group, anaralkyloxy group, a substituted aralkyloxy group, an aryloxy group, asubstituted aryloxy group, an acyl group, an acyloxy group, analkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonylgroup, an alkylenedioxy group, a hydroxy group, a nitro group, an aminogroup or a substituted amino group; R³ and R⁴, R⁴ and R⁵, R⁵ and R⁶, orR⁶ and R⁷, taken together, may form a fused ring, with the proviso thateither R³ or R⁷ is a hydrogen atom, to an asymmetric hydrogenation toproduce an optically active β-amino acid derivative of formula (5),

wherein * shows an asymmetric carbon atom, and R¹ to R⁷ have the samemeanings as mentioned above; 2) a step of amidating the optically activeβ-amino acid derivative of formula (5) above obtained in 1) above toproduce an optically active amide of formula (6),

wherein R¹, R³ to R⁷ and * have the same meanings as mentioned above, 3)a step of alkoxycarbonylating the optically active amide of formula (6)above obtained in 2) above to produce a compound of formula (7),

wherein R⁸ is a hydrocarbon group or a substituted hydrocarbon group,and R¹, R³ to R⁷ and * have the same meanings as mentioned above, and 4)a step of subjecting the optically active compound of formula (7) aboveobtained in 3) above to a cyclization to produce an optically activetetrahydroquinoline of formula (1) above.
 4. A method for producing anoptically active tetrahydroquinoline of formula (1),

wherein R¹ is a hydrocarbon group, a substituted hydrocarbon group orCOOR⁹ (R⁹ is a hydrocarbon group or a substituted hydrocarbon group), R⁴to R⁷ are each independently a hydrogen atom, a hydrocarbon group, ahalogen atom, a halogenated hydrocarbon group, a substituted hydrocarbongroup, an aliphatic heterocyclic group, a substituted aliphaticheterocyclic group, an aromatic heterocyclic group, a substitutedaromatic heterocyclic group, an alkoxy group, a substituted alkoxygroup, an aralkyloxy group, a substituted aralkyloxy group, an aryloxygroup, a substituted aryloxy group, an acyl group, an acyloxy group, analkoxycarbonyl group, an aryloxcarbonyl group, an aralkyloxycarbonylgroup, an alkylenedioxy group, a hydroxy group, a nitro group, an aminogroup or a substituted amino group; R⁸ is a hydrocarbon group, and *shows a asymmetric carbon atom, R⁴ and R⁵, R⁵ and R⁶, or R⁶ and R⁷,taken together, may form a fused ring, which method comprises thefollowing steps: 1) a step of subjecting an enaminoester of formula (4),

wherein R¹ is a hydrocarbon group, a substituted hydrocarbon group orCOOR⁹ (R⁹ is a hydrocarbon group or a substituted hydrocarbon group); R²is a hydrocarbon group or a substituted hydrocarbon group, R³ to R⁷ areeach independently a hydrogen atom, a hydrocarbon group, a halogen atom,a halogenated hydrocarbon group, a substituted hydrocarbon group, analiphatic heterocyclic group, a substituted aliphatic heterocyclicgroup, an aromatic heterocyclic group, a substituted aromaticheterocyclic group, an alkoxy group, a substituted alkoxy group, anaralkyloxy group, a substituted aralkyloxy group, an aryloxy group, asubstituted aryloxy group, an acyl group, an acyloxy group, analkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonylgroup, an alkylenedioxy group, a hydroxy group, a nitro group, an aminogroup or a substituted amino group; R³ and R⁴, R⁴ and R⁵, R⁵ and R⁶, orR⁶ and R⁷, taken together, may form a fused ring, with the proviso thateither R³ or R⁷ is a hydrogen atom, to an asymmetric hydrogenation toproduce an optically active β-amino acid derivative of formula (5),

wherein * shows an asymmetric carbon atom, and R¹ to R⁷ have the samemeanings as mentioned above; 2) a step of reacting the optically activeβ-amino acid derivative of formula (5) mentioned above with a carbamateof formula (8),H₂N—COOR⁸  (8) wherein R⁸ is a hydrocarbon group or a substitutedhydrocarbon group, to produce a compound of formula (7),

wherein R⁸ is a hydrocarbon group or a substituted hydrocarbon group,and R¹, R³ to R⁷ and * have the same meanings as mentioned above; and 3)a step of subjecting the optically active compound of formula (7) aboveobtained in 2) above to a cyclization to produce an optically activetetrahydroquinoline of the formula (1) mentioned above.